Detection of inflammatory bowel disease: diagnostic performance of cross-sectional imaging modalities

Different cross-sectional imaging techniques can be used as a diagnostic tool for the evaluation of inflammatory bowel disease (IBD). In this report the diagnostic performances of ultrasonography, magnetic resonance imaging and computed tomography in the detection of IBD and the evaluation of known IBD are described, together with a short update on patient preparation and imaging technique of the respective modalities discussed.
Introduction
Chronic inflammatory bowel disease (IBD) consists of two main subtypes, i.e., Crohn’s disease (CD) and ulcerative colitis (UC). During the last decades, the incidence of CD has continued to increase worldwide, reaching incidence rates ranging from 3.1 to 14.6/100,000 in North America and from 0.7 to 9.8/100,000 in Europe [1]. Incidence rates of UC differ greatly between studies and regions, varying from 1.5 to 24.5 per 100,000 person-years [1, 2].
Crohn’s disease can be localized in any part of the gastrointestinal tract, although the location of predilection is the terminal ileum, involvement of the terminal ileum is observed in 90% of the patients with small-intestinal CD, who in turn constitute 30–40% of all CD patients. In 40–55% of the patients both ileum and colon are affected, while in a minority (15–25%) only a colonic localization is observed.
The earliest change caused by CD occurs in the mucosa and submucosa and consists of hyperemia and edema. Tiny aphthoid or superficial ulcerations can be seen when disease progresses. In more severe disease, the disease extends transmurally with sometimes serosal involvement. In this stage, mucosal ulcerations merge to form deep longitudinal and transverse ulcerations while bowel wall thickening and narrowing of the bowel lumen can be observed due to significant mucosal edema and associated bowel spasms. In long-standing disease, chronic obstruction can develop due to scarring, luminal narrowing, and stricture formation. Extramural manifestations of CD are fistulas, abscesses, adhesions, creeping fat, and enlargement of lymph nodes.
Ulcerative colitis exclusively affects the colon with a predictable way of spreading from distal to proximal in a continuous manner; the rectum is often involved, but rectal sparing can be observed. In previous cases, small superficial erosions can be seen, whereas in more severe disease these ulcerations can be quite large. However, only in very severe disease they penetrate the muscularis layer. The mucosa is thickened because of round-cell infiltration in the lamina propria. In chronic UC, a marked hypertrophy of muscularis mucosae can be seen, causing contraction, shortening, and narrowing of the involved colon. The submucosa becomes thickened because of the deposition of fat or, in acute or subacute cases, edema [3, 4].
Diagnostic modalities
The gold standard examination for the small bowel traditionally has been small bowel barium examination (SBE), either by using an enteroclysis technique or by using small-bowel follow-through [5, 6]. SBE is invasive and burdensome, and requires an extensive bowel preparation (dietary restrictions, use of laxatives). Moreover, in the young population of CD patients, the ionizing radiation required for SBE limits the use of this technique for follow-up of disease.
The advent of video capsule endoscopy (VCE) and double-balloon endoscopy (DBE) has increased the diagnostic possibilities. For VCE a capsule is swallowed after a fasting period of up to 12 h and is propelled through the bowel by peristalsis. Thus, the mucosal surface of the small bowel can be depicted in detail (Fig. 1). However, with VCE there is no facility to increase visibility by insufflation of air or by tissue rinsing. Moreover, tissue sampling and therapeutic interventions are not possible. The use of VCE is contraindicated in patients with (suspicion of) obstruction due to the risk of capsule retention.
Fig. 1.VCE image of a 14-year-old male patient with known CD. VCE was performed as small-bowel disease was suspected. Image shows severe inflammation of the small bowel with a stenosis.
For DBE, a high-resolution video-endoscope with a flexible overtube is used. By alternately inflating and deflating two balloons attached to the overtube and endoscope the small bowel is threaded on the overtube. Both an oral and an anal approach are possible; for the oral approach no specific preparation is required, although patients are asked to fast for at least 6 h before the procedure. If the anal approach is used, bowel cleansing such as is employed for traditional colonoscopy is used. By using both the anal and oral approach, DBE allows visualization of the entire small bowel, with the possibility of obtaining tissue for analysis and the added advantage of the possibility of endoscopic therapy (e.g. dilatation of a stricture, cauterization of a bleeding site). For DBE conscious sedation is a necessity.
Traditionally, ileocolonoscopy (CS) with tissue sampling is considered to be the most valuable tool for diagnosis and follow-up of disease in the colon and terminal ileum [5, 7]. As UC solely affects the mucosa of the colon, CS would suffice for diagnosis of disease and evaluation of disease activity and extent. However, when strictures are present as a complication of disease, these might hamper execution of a complete examination, while in severe attacks of UC CS is relatively contra-indicated due to the increased risk of bleeding or perforation. For ileocolonic localizations of CD CS would suffice as well, although inspection of the terminal ileum is reported to fail in up to 27.8% of examinations [8, 9].
Cross-sectional imaging modalities
The trans- and extramural extent of IBD cannot be visualized with any of the abovementioned techniques. Much research has been directed toward the potential of cross-sectional imaging modalities for the diagnosis and evaluation of IBD as with these techniques the bowel lumen, the bowel wall and the extra-intestinal abdomen including the visceral fat, the lymph nodes and the vascular structures feeding and draining the bowel can be visualized. An added advantage of these techniques is the fact that they are limitedly to non-invasive.
Ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) are often used for the evaluation of the abdomen. While in the USA the technique of choice is CT, in Europe the focus is more on MRI and US. This inclination is reflected by the majority of CT studies on IBD patients originating from the USA, while the majority of published studies on MRI and US has been conducted in Europe.
Ultrasonography
Patient preparation and US technique
Patients are usually asked to fast for several hours before the scan to diminish peristaltic movements and the amount of intraluminal air; in the available literature the minimum fasting time described is 4 h, whereas overnight fasting is also sometimes employed. Usually, no additional dietary or cleansing measures are taken. Due to the limited patient preparation necessary and the non-invasive nature of this examination, US can be considered to be a relatively patient-friendly and straightforward examination.
Ultrasonography is mostly performed without the use of enteral contrast medium. In two recent studies, the effect of enteral contrast medium for diagnosis of IBD of the small bowel was investigated; higher sensitivity values were obtained when enteral contrast medium had been administered [10, 11]. In both studies the additional value of enteral contrast medium permitted detection of jejunal lesions that had escaped detection with conventional US. For colonic IBD, use of enteral contrast medium also increased accuracy [12, 13].
High-frequency transducers are preferred, such as 7.5 MHz [13–16].
The use of Doppler-US might provide helpful additional information on IBD, particularly on the degree of disease activity. Using Doppler-US the vascularity of the bowel wall can be assessed according to the intensity of color signals and/or by the analysis of Doppler curves (measurement of resistive index) obtained from vessels detected within the bowel wall. Measurement of flow parameters of the superior and inferior mesenteric arteries can also be performed.
Imaging criteria
The criterion that is most extensively used for the diagnosis of CD is bowel wall thickening. In most studies, the bowel wall is considered to be thickened when thickness exceeds 3 mm (Fig. 2). In a meta-analysis conducted by Fraquelli et al. [17] concerning US in CD the respective diagnostic accuracies of different cut-off values were compared; sensitivity for diagnosis of CD decreased using a cut-off value of 4 mm instead of 3 mm (from 88% to 75%), but specificity increased slightly (from 93% to 97%). Other features that are considered characteristic of CD on US are the presence of a stiff bowel wall, modification or disappearance of bowel wall stratification, presence of deep ulcers (seen as interruption of the submucosal hyperechoic rim by a hypoechoic tract), a reduction of peristalsis and loss of haustration in the colon. Extramural findings are fibrofatty proliferation, enlarged lymph nodes, and/or the presence of an abscess or fistula.
Fig. 2.A 14-year female patient with known CD and intermittent abdominal pain. US image shows the thickened wall of the terminal ileum (arrowheads) with some infiltration of the perivisceral fat.
Bowel wall thickening is considered to be a characteristic feature of UC as well. Mural stratification is preserved in most UC patients due to the superficial pattern of inflammation. This feature can be used to differentiate between CD and UC, although this was not regarded sufficient for differentiation in all studies on this topic [12, 13]. In long-standing UC a tubular appearance of the colon and loss of haustration can be seen.
Diagnostic accuracy of US
Most studies regarding diagnostic accuracy of US for diagnosis and follow-up of IBD have been conducted in the last decade. Although reported sensitivity and specificity values are high, with the state-of-the-art equipment diagnostic accuracy could possibly be higher than that previously reported.
In the hands of an experienced radiologist, US can be very accurate for the detection of IBD. Reported sensitivity values of US for the detection of IBD in patients with suspected disease vary from 76% to 92% [15, 18, 19]; specificity values are also high. In patients with proven IBD, reported sensitivity values for US are higher, probably reflecting a higher index of suspicion [10, 20]. Reported segmental sensitivity values are lower; these are below 78%, even if gray-scale US is combined with power Doppler [21, 22]. Regarding the detection of extramural complications, fistulas and abscesses can be identified accurately on US [23, 24] (Fig. 3).
Fig. 3.A 25-year-old female patient with known CD of the terminal ileum. A US image shows a large abscess (arrowheads) that was located ventrally and cranially of the bladder. B US image shows a fistula (arrowheads) that originated from the abscess.
Although many US studies have been carried out, most concerned either CD patients or both CD and UC patients, and reported accuracy values are usually applicable for both subgroups of disease. Although in the study by Limberg and Osswald [13] separate accuracy values are provided for US and CD, it is not clear from these data if accuracy values were obtained from post hoc separation of data. To our knowledge, as of yet no prospective study has been performed with predetermined imaging parameters to differentiate between CD and UC.
Although US can be used for the assessment of both small bowel and colon, disease localized in the duodenum and jejunum is often missed [18, 19, 25]. Moreover, the rectum and distal sigmoid cannot be visualized accurately due to their pelvic location. This makes US less suitable for the assessment of UC.
Doppler US has been proved useful in assessing whether IBD is in an active phase or in remission; significant correlations were found between Doppler parameters and disease activity, both in UC [26] and in CD [27]. However, the only distinction made was between active and inactive disease, meaning no conclusions can be drawn about the severity of active disease from these data. As of yet, there is no standardized scale to determine the degree of disease activity on US, neither for CD nor for UC.
The spatial resolution of US is not high enough to permit the detection of superficial pathology, making this modality less suitable for the diagnosis of early diseases when compared with SBE. Although SBE can reportedly be highly accurate when performed by skilled radiologists [28, 29], compared with VCE or DBE its sensitivity is low [30]. In this regard, comparison between US and VCE and/or DBE might be very interesting in order to determine the accuracy of US for small lesions and accuracy for bowel segments that are difficult to access. To our knowledge, no comparative studies have been performed as of yet.
Computed tomography
Patient preparation
Patients are usually asked to fast for several hours before the scan to diminish peristaltic movements [31–33]. In addition, in some institutions a bowel-cleansing regimen is applied, as a rule consisting of mild laxatives. Dietary restrictions are also often applicable. Although with this bowel preparation residual feces are usually present to some degree, the mural presentation of disease enables the identification of disease even if the bowel wall is partly obscured.
There is consensus as to the indispensability of enteral contrast medium for an abdominal CT examination for IBD. The contrast medium of choice should be neutral (meaning an attenuation value comparable with water), as a neutral contrast medium allows optimal distinction between bowel wall and lumen. While in some institutions enteral contrast medium is administered orally (CT enterography), in other institutions controlled distention is achieved by inflow of contrast medium through a nasojejunal catheter (CT-enteroclysis). Although by some authors CT-enteroclysis is propagated as the controlled infusion provides a more consistent distention of the small bowel than CT-enterography, especially of the jejunum [34], others report that with the right choice of contrast medium and correct timing of intake excellent distention of all small bowel loops can be obtained after the oral administration of contrast medium [31, 33]. In only one small study, CT enteroclysis and CT enterography were compared, but both the degree of luminal distention and the diagnostic accuracy did not show significant differences [35].
Imaging technique
Technical developments have allowed the widespread use of multi-slice scanners. With these scanners volumes can be scanned in a very short breath hold, allowing the acquisition of isotropic voxels for multiplanar reformatting. Thin slices should be used to permit the detection of subtle pathology.
Before CT enterography sometimes metoclopramide is given to increase gastric emptying and peristaltic movements of the small bowel [31]. The use of antiperistaltic drugs is not standard. In a recently published update on CT enteroclysis, Rajesh and Maglinte [32] report that in their institution all patients undergoing CT enteroclysis receive conscious sedation. Although this most probably decreases patient discomfort to a large degree, this can considerably increase the in-hospital time for patients as they will have to stay in a recovery unit after the procedure until the anesthetic effects have worn off.
Intravenous contrast medium should be administered for a comprehensive CT examination of the bowel. In a recent study, the optimal timing of scanning after the administration of intravenous contrast medium was determined; Schindera et al. [36] found that peak mural enhancement of normal small-bowel wall occurs on average about 50 s after contrast administration or 14 s after peak aortic enhancement.
Imaging criteria
The main feature considered indicative of both CD and UC is bowel wall thickening. Whereas in earlier studies cut-off values for pathological bowel wall thickening have varied between 2.5 mm and 10 mm, in recent publications of experts in the field bowel wall thickness exceeding 3 mm is described as pathological [31, 33] (Fig. 4). Mural thickening is not seen in early superficial disease, precluding CT from being a first-line examination for (suspicion of) superficial disease.
Fig. 4.A 60-year old female patient who underwent CT enterography for suspected bowel obstruction. Just 1 month earlier at ileocolonoscopy CD of the terminal ileum was discovered; the terminal ileum was not intubated because of the stenosis. Axial image shows the severely thickened bowel wall of the ileum (arrowheads) with only a pinpoint bowel lumen remaining.
Increased bowel wall enhancement after the administration of intravenous contrast medium is also considered as an indicative of active disease [37–39]. Whereas in earlier studies the only distinction regarding enhancement was between pathological enhancement (i.e., hyper-enhancement) and normally enhancing bowel walls, in a recent publication the degree of mural enhancement was found to correlate with disease activity [38].
Bowel wall enhancement can be transmural, but also layered. This layered enhancement pattern, which is represented by a thickened intestinal wall with a middle layer of low attenuation surrounded on each side by layers of higher attenuation, has been termed the target sign; this is due to the presence of edema or the deposition of fat in the submucosa.
Diagnostic accuracy of CT
The accuracy of CT has mainly been investigated for small-bowel disease. In suspected CD sensitivity was 83% when compared with SBE [40]. When compared with ileoscopy sensitivity values vary from 80% to 88% [34, 35, 41]. Segmental sensitivity of CT was somewhat lower (71.8%) in a study by Molnar et al. [42], comparing CT with SBE and CS.
Superficial lesions (such as aphthoid lesions) are not accurately visualized on CT, making CT less suitable as a first-line examination for the suspicion of mild disease. This was already evident from studies comparing CT with CS and/or SBE, but in a recent meta-analysis comparing CT with VCE was shown that the yield of CT compared with the yield of CE was 30% vs. 69% [43]. No comparative studies have been published regarding CT vs. DBE.
Extramural complications are well shown on CT, although the lower contrast resolution of CT makes this modality less suitable for the detection of fistulas and abscesses than MRI in patients with CD [44] (Fig. 5). In a recent study, the relationship between increased attenuation of perivisceral fat and disease activity was determined; one of the most specific markers of active disease was increased attenuation in the perivisceral fat [37].
Fig. 5.A 25-year-old female patient with known CD of the terminal ileum (same patient as pictured in Fig. 3). A CT-scan was performed to determine involvement of the small bowel. A Coronal image shows the abscess (arrowheads). B Axial image again shows the abscess again (arrowheads). C Coronal image shows the fistula (arrowhead).
Hardly any studies have focused on the accuracy of CT colonography for the detection of ileocolonic IBD. This is possibly partly due to the fact that for the rectal administration of contrast medium the rectum is obscured by the rectal catheter, precluding diagnosis of rectal IBD, specifically UC. It does seem clear that CTC is unable to detect ulcerative lesions; even diffuse inflammation with large ulcerations can be missed. CTC might however be useful in patients with colonic stenosis or narrowing [45, 46].
Magnetic resonance imaging
Patient preparation
While in some studies on MRI a period of several hours of fasting was deemed sufficient, in others full bowel cleansing was performed, as the reference standard, (i.e., CS) was performed on the same day. There is no consensus yet as to what constitutes the optimal bowel preparation for MRI. However, as a limited bowel preparation does not seem to negatively affect accuracy, it might be sufficient to limit the bowel preparation to a fasting period taking into account the patient-friendliness of the respective preparations.
Luminal distention by means of use of enteral contrast medium is indispensable for an adequate evaluation of the bowel as collapsed bowel can hide or mimic disease. As was the case with CT, for MRI of the small bowel contrast medium is either administrated by mouth or by enteroclysis. An advantage of MR enteroclysis over MR enterography is the fact that it allows fluoroscopic monitoring of the inflow of contrast medium and thereby provides functional information on bowel distensibility. An advantage of MR enterography is the fact that it can be considered more patient-friendly and also that no ionizing radiation is necessary. To our knowledge, only one study has been carried out in which both methods of contrast medium administration were compared. In this study by Schreyer et al. [47] all patients (n = 21) underwent both MRI enterography and MRI enteroclysis; no difference in accuracy compared with SBE was noted by the investigators (Fig. 6).
Fig. 6.A A 38-year-old female with complaints of vomiting and an iron-deficiency anemia who was suspected of CD and underwent MRI-enteroclysis to evaluate the small bowel. Coronal TrueFISP image shows good distention of jejunal bowel loops after controlled infusion of contrast medium. B A 12-year-old male patient with known CD who underwent MR enterography for the evaluation of the small bowel. Coronal TrueFISP image shows good distention of jejunal bowel loops after oral administration of contrast medium.
Whereas for MR enteroclysis mostly a methylcellulose suspension is used, for MR enterography many different contrast media have been tested. The main subdivision is between positive, negative, and biphasic contrast media. A biphasic contrast medium performs best for the identification of pathology on both T2-and T1-weighted sequences as adequate delineation between hypointense bowel wall and hyperintense lumen is seen on T2-weighted sequences while on T1-weighted images the enhancing bowel wall can be easily discriminated from the hypointense lumen. An artificial sugar-solution (mannitol or sorbitol) has been shown to cause good distention of small bowel loops with negligible side effects [48, 49].
Imaging technique
Mostly, both T2-weighted and T1-weighted sequences are used for the MRI evaluation of the bowel. On T2-weighted images the bowel wall can be appreciated and bowel wall stratification—if present—can be well apprehended. As feces can show bright signal intensity on T1-weighted sequences, it is important to perform a pre-contrast T1-weighted sequence in order to be able to determine whether high signal intensity was already present before intravenous contrast administration, indicating the presence of stool.
Another sequence that is propagated by many authors is the TrueFISp sequence, a sequence that is insensitive to motion and breathing artifacts. This sequence, that makes use of a T2/T1 ratio, adequately delineates the bowel wall and the mesentery, allowing adequate assessment of disease (Fig. 7). When combining a T2-weighted sequence or TrueFISP sequence and a T1-weighted sequence, a comprehensive MRI examination can be carried out in less than 30 min.
Fig. 7.A 18-year-old female patient with known CD. MRI-enterography was performed for suspicion of active CD of the neoterminal ileum. A Coronal TrueFISp image shows enlarged mesenteric lymph nodes (arrowheads). B Coronal TrueFISP image shows thickened bowel wall of the neoterminal ileum (arrowheads).
Imaging criteria
A bowel wall thickness exceeding 3 mm should be considered as an indicative of disease. Besides bowel wall thickening the most important criterion indicative of active IBD is pathological bowel wall enhancement after the administration of intravenous gadolinium. Bowel wall enhancement can always be seen as the bowel is a highly vascularized structure. However, in active IBD increased enhancement can be observed, due to the increased vascularization and the increased capillary leakage of the affected tissue (Fig. 8). In CD it has been hypothesized that the degree of enhancement correlates with the degree of disease severity, but this statement has not been extensively corroborated [50–53].
Fig. 8.A 12-year-old male patient with known CD who underwent MR-enterography for the evaluation of the small bowel (same patient depicted in Fig. 6b). Axial T1-weighted image shows pathological enhancement of thickened small-bowel loops after administration of intravenous contrast medium (arrowheads). Approximately, 1 m of small bowel (terminal jejunum, proximal ileum) was shown to be affected.
Bowel wall stratification can be observed on T2-weighted images as a bright line within the two dark stripes of the mucosal and muscularis propria layers, likely related to the presence of fat or edema in the submucosal layer. On fat-suppressed T2-weighted images it is possible to determine the nature of the bright signal as a persistent bright signal suggests the presence of edema, whereas complete suppression of the submucosal signal suggests fat infiltration and quiescent disease [54].
Extramural manifestations of disease that can be identified on MRI are fistulas, abscesses, fibrofatty proliferation, and enlarged lymph nodes.
Diagnostic accuracy
The accuracy of MRI of the small bowel has been extensively investigated. In many European institutions, conventional enteroclysis is increasingly being replaced by MRI enteroclysis or MRI enterography as MRI has proved to be highly accurate in both the detection of disease in patients with known IBD as in patients in whom IBD of the small bowel was suspected [52, 55, 56]. However, the studies that have been performed were mostly small and concerned selected populations with either a high suspicion of disease or known CD of the small bowel. Larger studies including the full spectrum of disease activity should be conducted.
As was the case with CT and US, MRI is not suitable for the detection of superficial disease due to the limited spatial resolution. This finding is corroborated by a study comparing MRI and VCE in patients with CD [57]. Significantly more inflammatory lesions were detected with VCE in the jejunum and partly in the ileum of patients with CD. However, these findings had no effect on the therapeutic approach of the individual patients. The accuracy of MRI has not been compared with DBE as of yet.
As mentioned before, MRI can be used for the evaluation of extramural disease. Due to the high contrast resolution abscesses are very conspicuous on T1-weighed fat suppressed images after the administration of intravenous Gadolinium. MRI is also very sensitive for the detection of fistulas [47, 52, 58] (Fig. 9).
Fig. 9.A 25-year-old female patient with known CD of the terminal ileum (same patient as pictured in Figs. 3 and 5). A Coronal T1-weighted image clearly shows the abscess (arrowheads) that was also depicted on US and CT. B Coronal T1-weighted image showing a fistula
In recent years, the accuracy of MRI for the detection of ileocolonic IBD has been investigated by means of MRI colonography. After administration of rectal contrast medium the colon (and sometimes the terminal ileum) was assessed for disease. Conflicting results were reported: while in one study high accuracy values were reported [59], in others segmental sensitivity values were around 32% [60, 61].
Regarding the accuracy of MRI in differentiation between CD and UC conflicting results have been reported; while some authors report that based on the location of inflammatory changes, the degree of involvement, the continuity or discontinuity of disease, and the presence of complications it was possible to differentiate between CD and UC [51, 62], others report a limited value in differentiation of disease [63].
Theoretically, a whole-bowel examination would be possible with MRI, by the administration of contrast medium orally and rectally. This has been attempted [64, 65] and was deemed feasible. More research is needed to establish the diagnostic value of this combined approach. At the moment, MRI colonography does not seem to be able to replace CS.
Discussion
Compared with conventional imaging methods, CT, US, and MRI are accurate methods for the detection of IBD of the small bowel, both in patients suspected of disease as in patients with known IBD. Although subtle lesions cannot be depicted with any of these modalities, clinically more relevant findings can be accurately depicted. Therefore, cross-sectional imaging should be incorporated in a comprehensive clinical evaluation of suspected IBD and for follow-up of CD. The exact role cross-sectional imaging techniques can play for follow-up in UC should be more extensively studied.
As US is easily accessible, widely available, and inexpensive, it is recommended to use abdominal US as first-line modality in patients with suspected IBD of the small bowel. MR enterography would be a good alternative, especially as the assessment of the degree of disease activity can be better performed on MRI than on US. Although CT enterography is a very accurate technique and is used in many institutions, its role in IBD is limited by the ionizing radiation needed, especially due to the repetitive use for follow-up in often young individuals. If possible, it might be advisable to reserve this technique for patients in whom imaging is needed at very short notice as CT enterography can be performed very fast and is readily available.
Although VCE has shown to be more accurate in depicting subtle lesions in the small bowel than MRI or CT, its role should be limited as of yet as the true benefit of VCE is not clear yet. As there are presently no standardized criteria for the diagnosis of CD with VCE, definitions with regard to what constitutes a positive finding might differ between studies. Moreover, the clinical significance of finding a single mucosal break or a few superficial aphthous lesions is not clear yet. Also, specificity and positive predictive values for VCE have not been established. At this time, it might be good to reserve VCE as a second-line modality if cross-sectional imaging has not shown abnormalities but the suspicion of disease remains standing despite these negative findings.

inflammatory bowel disease
diagnostic performance
ultrasonography
magnetic resonance imaging
computed tomography


Short- and long-term mortality after acute myocardial infarction: comparison of patients with and without diabetes mellitus

Aims To compare short- and long-term mortality after a first acute myocardial infarction (AMI) in patients with and without diabetes mellitus. Methods and results A nationwide cohort of 2,018 diabetic and 19,547 nondiabetic patients with a first hospitalized AMI in 1995 was identified through linkage of the national hospital discharge register and the population register. Follow-up for mortality lasted until the end of 2000. At 28 days and 5 years respectively, absolute mortality risks were 18 and 53% in diabetic men, 12 and 31% in nondiabetic men, 22 and 58% in diabetic women, and 19 and 42% in nondiabetic women. Crude mortality was significantly higher in diabetic patients than in nondiabetic patients in both men (28-day hazard ratio (HR) 1.55; 95% confidence interval (CI) 1.32–1.81, 5-year HR 2.01; 95% CI 1.84–2.21) and women (28-day HR 1.19; 95% CI 1.03–1.37, 5-year HR 1.53; 95% CI 1.40–1.67). After multivariate adjustment, risk differences became nonsignificant at 28 days, but diabetes was still associated with a significantly higher long-term mortality in both men (28-day HR 1.16; 95% CI 0.99–1.36, 5-year HR 1.49; 95% CI 1.36–1.64) and women (28-day HR 1.12; 95% CI 0.97–1.28, 5-year HR 1.39; 95% CI 1.27–1.52). The interaction between diabetes mellitus and gender did not reach significance in the analyses. Conclusion Our findings in an unselected cohort covering a complete nation show a significantly higher long-term mortality after a first acute myocardial infarction in diabetic patients. Yet, short-term mortality is not significantly higher in diabetic patients. Risks appear to be equally elevated in men and women.
Introduction
It is well established that patients with diabetes mellitus (DM) have a higher short-term mortality after acute myocardial infarction (AMI) than patients without DM. Several recent studies have found that hospital, 28-day and 1-year mortality after AMI was approximately 1.5–2 times higher in diabetic patients [1–3]. As it is known that most patients survive beyond this period, it is important to study the difference in long-term survival after an AMI between diabetic and nondiabetic patients as well. Survival after an AMI may be particularly worsened beyond the poorer prognosis already conferred by the presence of DM itself, as diabetic patients with an AMI may experience more severe coronary heart disease and more complications (left ventricular dysfunction and heart failure, significant ventricular arrhythmias) than nondiabetic patients with an AMI [2, 3]. There are relatively few recent studies that address differences in long-term prognosis after an AMI between diabetic and nondiabetic patients with follow-up lasting through the second half of the 1990s [4–8]. Moreover, data largely originate from clinical trials or single centers [4, 5, 7]. These studies reported that DM is independently associated with long-term mortality [4–8].
The aim of the present study was to compare short- and long-term mortality after a first hospitalized AMI in patients with and without DM encompassing the entire country by using data from linked national registers.
Methods
Design
The study methods, including enrollment of the study population, have recently been described in detail [9]. In brief, cases of first hospitalized AMI in the Netherlands in 1995 were identified by linkage of the Dutch national hospital discharge register and the Dutch population register. Thus, the study included a total of 21,565 patients hospitalized for a first AMI in 1995. These patients had not been previously hospitalized for AMI from 1991 to 1995. Information about demographic characteristics, medical history and hospital outcomes was obtained from the hospital register and the population register. All general and academic hospitals and most specialty hospitals participate in the hospital register. For each hospital admission a new record is created in the hospital register, including the following information: date of birth, gender, numeric part of postal code, hospital-specific patient identification code, type of hospital, admission date and principal and secondary diagnoses of the admission. The principal diagnosis is determined at discharge and is in retrospect the main reason for admission. The diagnoses are coded using the ninth revision and clinical modification of the International Classification of Diseases (ICD-9-CM) [10]. The population register contains information on all registered persons living in the Netherlands, including date of birth, gender, current address, postal code, nationality, native country (both of registered person and his/her parents), date of death and date of emigration. Patients whose parents were both born in the Netherlands were classified as native Dutch. Patients were classified as having a history of cardiovascular disease or having DM when cardiovascular disease (ICD-9-CM [10] codes 390–459 and subcategories, principal diagnoses) or DM (ICD-9-CM [10] code 250 and subcategories, principal and secondary diagnoses) was registered during previous hospital admissions in 1991–1995 and in case of DM also during the index admission in 1995. Data on mortality of the patients were derived by linking their records with the population register and the cause of death certificates. In the population register, it is recorded when a registered person has died. Linkage of the population register with the cause of death certificates yielded information on primary causes of death.
Data analysis
Survival time was calculated as the time from the initial AMI admission date in 1995 to the date of death from any cause, or a patient was censored at the date of loss to follow-up in the population register (4% of patients, e.g. in case of emigration) or the end of study at December 31, 2000, whichever came first. Crude short-term (28-day), 1-year and long-term (5-year) mortality risks were computed for diabetic and nondiabetic patients. Cox proportional hazard analyses were used to examine the association between DM and overall survival in men and women. DM (yes/no) and other predictors, including age (continuous), previous cardiovascular disease (yes/no) and ethnic origin (native or non-native Dutch) were included in the models. Furthermore, Cox proportional hazards models were used to determine whether gender, age, previous cardiovascular disease and ethnic origin were independently associated with overall survival in patients with DM and patients without DM. Interaction terms were included in the models to assess the interaction of gender with DM, age with DM and age with gender.
Results
The characteristics of the diabetic and nondiabetic patients with a first AMI are presented in Table 1. Most of the diabetic patients were women (52%), whereas most of the nondiabetic patients were men (69%). In both diabetic and nondiabetic patients, women were older and had a longer duration of hospital stay than men. Diabetic patients were older and more likely to have previous cardiovascular disease (excluding AMI) compared to nondiabetic patients.
Table 1Characteristics of first acute myocardial infarction patients with and without diabetes mellitusPatients with diabetes mellitusPatients without diabetes mellitusMenWomenMenWomenNumber of patients9691,04913,4946,053Age at admission (years)    Mean (standard deviation)68.7 (11.0)73.2 (10.3)64.0 (12.3)71.6 (12.0)Prior admission for CVD (%)31.731.016.816.3Type of hospital (%)    Academic6.76.16.25.7    General93.393.993.894.3Length of stay (days)    Mean (standard deviation)11.1 (8.5)12.5 (11.8)9.7 (7.4)10.6 (9.7)    Median10.010.09.09.0    P25–P75a7.0–13.06.0–16.06.0–12.06.0–13.0Native ethnic origin (%)87.088.090.090.0CVD = cardiovascular disease, excluding acute myocardial infarctiona25th and 75th percentile
During admission, 18% of the diabetic patients (men 16%, women 20%) and 13% of the nondiabetic patients (men 11%, women 18%) died. In both diabetic and nondiabetic patients, AMI was the most frequent cause of death (during hospitalization 71 and 82%, respectively, and during 5 years of follow-up 39 and 45%, respectively).
Table 2 shows the higher absolute short- and long-term mortality risks for diabetic patients compared to nondiabetic patients in men and women.
Table 2Short- and long-term mortality in patients with a first hospitalized acute myocardial infarction (AMI) in the Netherlands in 1995 stratified by gender and presence of diabetes mellitusMenDiabetic patients (n = 969)Non-diabetic patients (n = 13,494)Deaths (n)Deaths (%)Deaths (n)Deaths (%)At 28 days17017.5 (15.1–19.9)1,55511.5 (11.0–12.1)At 1 year28929.8 (26.9–32.7)2,31617.2 (16.5–17.8)At 5 years51653.3 (50.1–56.4)4,11630.5 (29.7–31.3)WomenDiabetic patients (n = 1,049)Non-diabetic patients (n = 6,053)Deaths (n)Deaths (%)Deaths (n)Deaths (%)At 28 days23522.4 (19.9–24.9)1,15219.0 (18.0–20.0)At 1 year36835.1 (32.2–38.0)1,62626.9 (25.7–28.0)At 5 years61158.2 (55.3–61.2)2,53841.9 (40.7–43.2)Figures are numbers and percentages of deaths (95% confidence intervals in brackets) based on actuarial life table method
Crude short- and long-term mortality was significantly higher in diabetic patients than in nondiabetic patients in both men (28-day hazard ratio (HR) 1.55; 95% confidence interval (CI) 1.32–1.81, 5-year HR 2.01; 95% CI 1.84–2.21) and women (28-day HR 1.19; 95% CI 1.03–1.37, 5-year HR 1.53; 95% CI 1.40–1.67). When differences in age and other covariates between diabetic and nondiabetic patients were taken into account, risk differences became nonsignificant at 28 days, but DM was still associated with a significantly higher long-term mortality in both men and women (Table 3). The interaction between gender and DM for 28-day, 1-year and 5-year mortality did not reach significance in the analyses, indicating that risks are equally elevated among men and women.
Table 3Multivariate analysis of the association between diabetes mellitus and short- and long-term mortality in first acute myocardial infarction patients (n = 21,565) by gender and ageAge (years)Follow-up duration28 days1 year5 yearsMen<601.41 (0.79–2.53)1.38 (0.86–2.23)1.83 (1.34–2.51)60–691.46 (1.02–2.08) 1.73 (1.31–2.28)1.80 (1.46–2.21)70–791.04 (0.80–1.36)1.16 (0.94–1.42)1.42 (1.23–1.65)≥801.11 (0.82–1.50)1.32 (1.04–1.66)1.37 (1.14–1.65)All ages1.16 (0.99–1.36)1.33 (1.17–1.50)1.49 (1.36–1.64)Women<602.06 (1.09–3.88)2.16 (1.25–3.75)2.13 (1.40–3.25)60–691.38 (0.92–2.06)1.65 (1.19–2.29)1.99 (1.57–2.54)70–790.94 (0.72–1.22)1.12 (0.92–1.37)1.38 (1.19–1.60)≥801.15 (0.94–1.42)1.18 (0.99–1.40)1.25 (1.09–1.44)All ages1.12 (0.97–1.28)1.23 (1.09–1.37)1.39 (1.27–1.52)TotalAll ages1.13 (1.02–1.26)1.27 (1.17–1.38)1.44 (1.35–1.53)Figures are hazard ratios (95% confidence intervals in brackets) with nondiabetic patients representing the reference groupResults from Cox proportional hazards analyses with diabetes mellitus, previous cardiovascular disease and ethnic origin (age- and gender-specific hazard ratios) and age (gender-specific overall hazard ratios) and gender (overall hazard ratios) included in the model
In the multivariate analyses, gender differences in mortality in nondiabetic patients varied over time with a higher mortality in women at 28 days and a higher mortality in men at 5 years (28-day HR 1.11; 95% CI 1.03–1.20, 5-year HR 0.93; 95% CI 0.88–0.98). Largely comparable, yet not significant, gender differences in mortality were found in diabetic patients (28-day HR 1.09; 95% CI 0.89–1.34, 5-year HR 0.93; 95% CI 0.82–1.04).
Discussion
Our study provides nationwide estimates of the difference in mortality after a first hospitalized AMI between diabetic and nondiabetic patients. Long-term mortality was significantly higher in diabetic patients than in nondiabetic patients. Yet, there were no significant differences in short-term mortality. Risks appeared to be equally elevated in men and women.
Some aspects of the study need to be addressed. In our study, the presence of DM was merely based on information from hospital admissions and on a retrospective period of maximal 5 years. As a result, the estimate of the effect of DM is likely an overestimate due to selection of the more severe cases (those hospitalized with or due to DM), while a fairly limited number of people with less severe stages of DM (not requiring hospital care) will be diluted in the large group of people who truly did not have DM.
In our study, we were able to jointly evaluate a number of predictors of mortality using information from the hospital register. However, we were unable to examine the contribution of other predictors on our outcomes, including other risk factors, comorbidity and treatment, as registration in the hospital register is limited. Yet, this does not invalidate the finding that DM is related to a worse long-term prognosis in patients with a first AMI, as confounding is not an issue in descriptive (prognostic) research [11]. However, if cofactors such as the presence of poorly treated hypertension or dyslipidemia become the focus of investigation, the lack of more detailed information from the hospital register renders such analyses impossible.
In our study, the percentage patients with a cardiovascular history (other than AMI) was about 2 times higher in diabetic patients than in nondiabetic patients. To be sure that the worse prognosis of diabetic patients compared to nondiabetic patients was real and not merely a reflection of the difference in cardiovascular history, we repeated the analyses in diabetic and nondiabetic patients without a cardiovascular history. These analyses yielded similar findings.
The present study involved hospitalized first AMI patients. Out-of-hospital deaths from first AMI were not included. A substantial and possibly selective mortality with regard to DM might have preceded the baseline of our study, e.g. if DM were more prone to out-of-hospital death [2] then this may result in less clear differences over the rest of the first 28 days, because the early deaths were not recorded. Therefore, the study population does not represent (the diabetes distribution of) all first AMI patients in the Netherlands, but specifically hospitalized first AMI patients, and results might differ from population-based studies, which usually manage to include the out-of-hospital deaths.
As data on patients without an AMI were not available, we were not able to compare the effect of DM on mortality in patients without an AMI with the effect in patients with an AMI, i.e. whether survival after an AMI is particularly worsened beyond the poorer prognosis already conferred by the presence of DM itself.
The strength of our study lies in the validity of the registries and linkage methods, the large size and lack of selection of the cohort and the long duration of follow-up. Recently, it was shown that 99% of the personal, admission and discharge data and 84% of the principal diagnoses (validated through medical record review by medical specialists) were correctly registered in a random sample of all hospital admissions registered in the hospital register [12]. Furthermore, over 97% of the uniquely linked hospital admissions resulting from linkage of the hospital register with the population register were shown to be correctly linked [13].
Results from different studies regarding differences in mortality between diabetic and nondiabetic patients are conflicting. Consistent with our findings, it has been reported that DM has no independent predictive value on short-term mortality [14]. Yet, several other recent studies showed that short-term (<1 year) mortality after AMI was significantly higher (approximately 1.5 to 2 times) in diabetic patients compared with nondiabetic patients [1–3, 15]. Weitzman et al. [16] found a significant higher 1-year mortality in diabetic men (odds ratio (OR) 1.5; 95% CI 1.2–1.9), but no significant association in women. Recent studies regarding differences in long-term mortality (follow-up ranging from 4 to 10 years) after AMI showed an approximately 1.5–2.5 higher risk of dying in diabetic patients [4–8, 17]. Ishihara et al. [18] showed that DM was an independent predictor of 10-year mortality in patients with single vessel disease (OR 1.81; 95% CI 1.27–2.54), but in patients with multivessel disease the influence of DM was nonsignificant (OR 1.17; 95% CI 0.85–1.60). Melchior et al. [5] reported that the difference in mortality after AMI between diabetic and nondiabetic patients increased with time (relative risk ranging from 1.03 [95% CI 0.81–1.31] at 30 days to 1.43 [95% 1.24–1.66] at 2 months-3 years and 1.74 [95% CI 1.36–2.23] at 7–9 years in patients admitted between 1990 and 1992).
We found no significant differences in short- and long-term mortality after a first AMI between men and women in diabetic patients. A few other studies examined gender differences in mortality after an AMI in diabetic patients. Crowley et al. [19] found that women with DM were at increased risk of hospital death compared to men (OR 1.37; 95% CI 1.08–1.75), but no significant gender difference in 1-year mortality (HR 1.25; 95% CI 0.99–1.58) and 10-year mortality (hazard ratio 1.00; 95% 0.99–1.58) was found. Two other studies showed a higher short-term (hospital or 28-day) mortality in women [2, 20].
The higher risk of long-term mortality in first AMI patients with DM reinforces the importance of vigorous preventive measures by lifestyle advice and drugs in these patients. Currently, achievement of lifestyle and risk factor goals for reducing mortality in diabetic patients with AMI is poor, as illustrated by Pyorala et al. [21] who reported that 20% of diabetic patients continued to smoke, 43% were obese, 57% had hypertension and 55% had hypercholesterolemia at least 6 months after hospitalization for coronary heart disease. A long-term, intensive approach consisting of behavior modification and pharmacologic therapy aimed at multiple risk factors is necessary, as it has been shown that this results in an impressive reduction in cardiovascular complications in patients with DM [22].
In conclusion, our findings in an unselected cohort covering a complete nation show that diabetic patients are at an increased risk of long-term mortality after a first acute myocardial infarction. Yet, there are no significant differences in short-term mortality. Risks appear to be equally elevated in men and women. These results stress the importance of secondary prevention by lifestyle advice and drugs in diabetic patients after a first AMI.

mortality
myocardial infarction
diabetes mellitus
survival
prognosis
registries
epidemiology


Serial O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma

Purpose Intracavitary radioimmunotherapy (RIT) offers an effective adjuvant therapeutic approach in patients with malignant gliomas. Since differentiation between recurrence and reactive changes following RIT has a critical impact on patient management, the aim of this study was to analyse the value of serial O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET scans in monitoring the effects of this locoregional treatment.
Introduction
The life expectancy of patients with high-grade gliomas, in particular glioblastoma multiforme, is still very poor. Standard treatment including surgery, radiation therapy and, if suitable, systemic chemotherapy results in median survival times ranging between 1 year for glioblastoma and about 3 years for anaplastic astrocytoma [1, 2]. Standard treatment is not able to control tumour progression for a longer period since in most cases microscopic tumour cell clusters located in the peritumoural brain tissue are left and become the starting point for (usually) early tumour recurrence [3, 4]: complete surgical resection or eradication by subsequent conventional radiation therapy is usually impossible. To overcome these limitations, more specific approaches for brain tumour treatment have been introduced, such as additional targeted radiotherapy, e.g. in form of a locoregional radioimmunotherapy (RIT) [5–9]. The infusion of radiolabelled monoclonal antibodies directly into the postsurgical resection cavity after surgery has enabled the delivery of high radiation doses to the affected area without harming the surrounding normal brain tissue or distant organs.
Treatment efficacy can be evaluated by different neuro-imaging modalities. Conventional magnetic resonance imaging (MRI) and computed tomography (CT) assess morphological parameters such as changes in tumour size, oedema or contrast enhancement. However, these changes and alterations in blood-brain barrier properties are not always related to tumour regrowth; rather, they can also represent non-specific inflammatory treatment effects and radiation or tumour necrosis, especially after locoregional administration of high-dose radiation [10–12]. Functional imaging methods have been proposed as an alternative for monitoring treatment and are claimed to be more specific than structural imaging methods.
Positron emission tomography (PET) using radiolabelled amino acid analogues, particularly [methyl-11C]-l-methionine (MET) and, in recent years, O-(2-[18F]fluoroethyl)-l-tyrosine (FET), has been employed in numerous metabolic studies of malignant brain tumours [13–21]. Since amino acid uptake has been shown to be increased relative to normal brain tissue in most low- and high-grade tumours, it has gained an important role in the diagnostic work-up of brain tumours [21–24]. PET using MET or FET has also been shown to differentiate reliably between tumour recurrence and post-therapeutic benign lesions after standard treatment modalities like surgery, external radiation therapy or chemotherapy [15, 16, 20, 25–28]. In a recent study, FET PET was evaluated for the first time in a novel locoregional therapeutic approach, for the purpose of monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma. Preliminary data in a small patient group suggested that FET PET seems to fulfil the clinical requirement for a method that is sensitive enough to assess therapeutic effects early and to distinguish between harmless post-therapeutic changes and tumour regrowth after this aggressive locoregional approach [29].
The aim of the present study was to evaluate the diagnostic value of FET PET in another locoregional approach, namely in monitoring the therapeutic effects of locoregional RIT following intracavitary administration of 131I- or 188Re-labelled monoclonal anti-tenascin antibodies (TN-mAb).
Materials and methods
Patients
Twenty-four patients (9 females, 15 males) with a mean age of 49±14 years and histopathologically proven tenascin expression of malignant gliomas (5 anaplastic astrocytomas, 19 glioblastomas) were included in the study. All patients had undergone primary surgery on the tumour or re-operation of tumour recurrence with implantation of an Ommaya reservoir into the resection cavity. Primary surgery had been followed in 23 of the 24 patients by external radiation therapy and in six patients by additional systemic chemotherapy.
In 7 of the 24 patients, small residual tumours with an average diameter of less than 1 cm had to be left because of their location in high-risk and functionally important areas. In 17 patients no obvious tumour was seen on baseline MRI examinations. Patients underwent one to five cycles of intracavitary RIT with 131I-labelled (n=19) or 188Re-labelled (n=5) murine TN-mAb (BC4, which is directed against the EGF-like repeats of human TN) at 6- to 8-week intervals (maximal cumulative activity 5,740 MBq for 131I and 470 MBq for 188Re). In 20 patients, serial FET PET and MRI scans were performed preceding every RIT cycle and at 3-month intervals after the end of RIT in order to detect tumour recurrence and to monitor the therapeutic effects. In the remaining four patients, follow-up with serial FET PET scans was not started until 10, 12, 17 and 33 months after the end of RIT. Altogether, a total of 119 PET scans were performed.
PET studies
FET PET scans were obtained with a Siemens ECAT EXACT HR+ scanner. To obtain standardised metabolic conditions, patients fasted for a minimum of 6 h before performing the PET scan. The scanner acquires 63 contiguous transaxial planes, simultaneously covering 15.5 cm of axial field of view. After a 15-min transmission scan (68Ge sources), 180 MBq [18F]FET was injected intravenously. Since FET accumulates and reaches a peak in malignant gliomas within 15–20 min after injection and only slowly decreases afterwards [14], a static PET study from 20 to 50 min post injection (three added frames of 10 min each, 128×128 matrix, 3D acquisition) was acquired to obtain adequate count rate statistics. Images were reconstructed by filtered backprojection using a Hann filter with a cutoff frequency of 0.5 Nyquist and corrected for scatter and attenuation. For semiquantitative evaluation, data were transferred to a HERMES work station (Hermes Medical Solutions, Sweden) and the slice with the highest FET uptake around the former resection cavity was evaluated. For this slice, maximal uptake (maximal counts within the tumour: TUmax) was determined and the ratio to the background (BG) was calculated. For background information, the mean uptake within a 70% isocontour threshold ROI mirrored to the opposite non-tumour-bearing hemisphere was determined.
Statistical analysis
The diagnostic performance in differentiating between recurrence and tumour-free status was assessed by receiver operating characteristic (ROC) analyses [30, 31]. For this purpose, data of serial PET scans were separately categorised into true- and false-positive and true- and false-negative findings using clinical follow-up or the results of histopathology as the gold standard. Then sensitivity (SN) and specificity (SP) pairs as a function of the respective decision thresholds were plotted as ROC curves to describe the inherent discrimination capacity of the diagnostic system and to define the optimal threshold for decision making. The threshold was considered optimal when the sum of paired values for SN and SP reached a maximum in two evaluations: the analysis of all performed scans (n=119) and the analysis of only that scan of each patient which presented with the highest uptake value during the entire follow-up period.
In addition, SN and SP values are given for a visual analysis using nodular versus non-nodular FET uptake as the criterion to distinguish between patients with tumour recurrence and tumour-free patients.
The duration of progression-free survival after the first RIT cycle was computed according to the Kaplan-Meier method using the SPSS for Windows (SPSS, Version 13.0, Chicago, IL) statistics package. Two groups were compared, those with maximal individual TUmax/BG ratios above ≥2.4 and those with ratios below <2.4, which was considered the threshold value for best differentiation between recurrent tumour and reactive post-therapeutic changes. Statistical differences between the two curves were tested using log rank and Breslow tests.
Results
Our clinical experience with RIT has been reported previously. We observed substantially prolonged survival times for patients who received RIT (n=37: a larger number than in this study) compared with a similarly treated group without additional RIT [5]. Therefore, readers are referred to this previous article for information on the clinical findings associated with this form of therapy; here we shall focus on the role of FET PET during follow-up only.
During the study period, 17 of the 24 patients ultimately presented with tumour progression while seven were considered tumour free. For the latter group, Table 1 summarises patient characteristics, number and time points of RIT cycles and cumulative activity, number of serial PET scans with FET uptake ratios at baseline and last follow-up, and patient survival after initial surgery. The tumour-free status was documented by biopsy in two patients (these patients presented with contrast enhancement on MRI which was highly suspicious for recurrence) and by stable clinical follow-up for between 23 and 87 months after initial surgery in the other five. Six of these seven patients demonstrated slightly increasing homogeneous FET uptake surrounding the resection cavity without any signs of additional nodular uptake; this uptake presented with a peak (baseline TUmax/BG 1.78±0.30, peak TUmax/BG 2.07±0.25, mean±SD) up to 18 months after RIT, followed by stable or decreasing values (last follow-up TUmax/BG 1.63±0.22; representative example in Fig. 1). One of these six patients unfortunately decided to discontinue the follow-up with FET PET 4 months after RIT. However, this patient was clinically followed and showed a stable course over 27 months after RIT and 35 months after initial surgery. In one of the seven patients with slightly increased stable and homogeneous FET uptake, RIT had been completed about 3 years prior to the beginning of FET PET monitoring; therefore the post-therapeutic phase of increasing FET uptake and its peak were probably missed. The peak values of TUmax/BG observed in tumour-free patients corresponded to the threshold value of 2.4 for TUmax/BG ratio as assessed by ROC analyses which allowed best differentiation between post-therapeutic reactive changes and tumour recurrence. In this small patient group, the extent and changes of FET uptake over time following RIT seemed to be independent of the delivered radiation dose since the peak TUmax/BG ratio reached similar levels in all patients. Furthermore, the time point of the peak uptake, which ranged between 2 and 18 months, also showed no obvious relation with the dose administered.
Table 1Patient and tumour characteristics and therapeutic details of tumour-free patientsAge (yrs)SexWHOSurgeryRIT cyclesCum. activity (MBq)/nuclideRITNo. of PET scansTUmax/BG: baselineTUmax/BG: peak TUmax/BG: last follow-up Survival (mo.) post surgerySerial FET PET monitoring started after the end of RIT36fIII05/9922,460/131I10/99–11/999–2.4 (02/01)1.5 (01/05)77 (l.c.)39mIII10/9855,740/131I05/99–01/008–2.3 (09/01)1.5 (10/05)85 (l.c.)37fIV03/0011,270/131I11/0012–2.1 (04/02)1.5 (02/05)66 (l.c.)54fIV08/9833,490/131I04/99–08/995–peak missed1.6 (05/05)87 (l.c.)Serial FET PET monitoring during and after RIT27fIV08/0111,280/131I03/0232.0 (02/02)2.2 (04/02)2.0 (06/02)35 (l.c.)22fIV01/0433,560/131I10/04–02/0561.4 (09/04)2.1 (04/05)1.8 (09/05)21 (l.c.)40fIV11/031380/188Re05/0471.4 (04/04)1.7 (03/05)1.4 (09/05)23 (l.c.)l.c. last contactFig. 1Serial MRI and FET PET scans of a 36-year-old woman after surgery for an anaplastic astrocytoma WHO III and following two RIT cycles (10/99 and 11/99 with 2,460 MBq 131I-TN-mAb). The patient was clinically tumour free at follow-up for up to 77 months after surgery. Slight linear contrast enhancement surrounding the small tumour cavity in the right central area is observed on MRI. On FET PET there is slightly increasing homogeneous FET uptake surrounding the cavity (which in this particular case mimics a more focal appearance owing to the small lesion size in combination with the limited resolution of the PET scanner), peaking 15 months after RIT (02/01) and decreasing during further follow-up. The respective TUmax/BG ratios are given below the PET images
Among the 17 of 24 patients who ultimately presented with tumour progression, ten experienced tumour recurrence and seven, regrowth of residual tumour. These diagnoses were histopathologically proven by stereotactic biopsy in five patients and by re-operation in three patients. In the remaining nine patients, suspected tumour regrowth or recurrence was assumed because of concordantly increasing contrast enhancement on MRI and clinical deterioration. Table 2 summarises the characteristics and results of patients with progressive disease. The ten patients without obvious tumour at baseline initially presented with normal ratios (TUmax/BG 1.64±0.26) but showed focally increasing FET uptake values, resulting in pathological ratios during follow-up (TUmax/BG 2.67±0.43). A representative example is shown in Fig. 2. In seven patients with known residual tumour on the baseline scan, further FET PET investigations demonstrated pathological ratios which were stable or increased over time (baseline TUmax/BG 2.49±0.42; last follow-up TUmax/BG 3.04±0.49). Six of these seven patients showed pathological contrast enhancement on baseline MRI as well. Most interestingly, in one of the seven patients (with anaplastic astrocytoma WHO grade III), MRI was rated as normal owing to the lack of contrast enhancement, whereas the concomitant PET scan showed pathological focal FET uptake ventral of the cavity, clearly indicating recurrence. This was proven by stereotactic biopsy. This patient underwent re-operation of this area, but unfortunately developed another tumour manifestation distant from the primary location that showed contrast enhancement on MRI as well (Fig. 3).
Table 2Patient and tumour characteristics and therapeutic details of patients with tumour recurrence or regrowth of residual tumour during follow-upAge (yrs)SexWHOSurgeryRIT cyclesCum. activity (MBq)/nuclideRITNo. of PET scansTUmax/BG: baselineTUmax/BG: last follow-up Survival (mo.) post surgeryPatients without obvious tumour at baseline followed by tumour recurrence40mIII10/0034,510/131I05/02–10/0261.5 (12/01)2.5 (03/03)36 (†)53mIV08/0111,690/131I03/0221.7 (01/02)3.1 (04/02)19 (†)46fIV11/0134,550/131I07/02–01/0361.5 (07/02)2.0 (09/03)26 (†)70mIV04/0323,020/131I02/04–06/0441.8 (02/04)2.7 (09/04)22 (†)69mIV05/042470/188Re07/04–10/0442.1 (07/04)3.3 (03/05)13 (l.c.)55mIV07/0233,060/131I11/03–03/0452.0 (09/03)2.1 (09/04)34 (†)61mIV12/0211,770/131I10/0321.6 (08/03)2.8 (12/03)17 (l.c.)56mIV04/0311,850/131I10/0371.6 (10/03)2.5 (02/05)24 (l.c.)37fIII04/0134,130/131I01/05–05/0551.2 (12/04)2.4 (07/05)54 (l.c.)39fIV03/0421,420/131I07/04–10/0461.6 (07/04)2.8 (07/05)19 (l.c.)Patients with small residual tumour at baseline followed by tumour progression30mIII02/0111,870/131I07/0242.6 (07/02)4.0 (12/02)25 (†)61mIV04/0034,250/131I09/01–12/0133.3 (09/01)3.6 (12/01)25 (†)60mIV02/0122,670/131I12/01–01/0232.5 (12/01)2.6 (03/02)28 (†)59mIV05/031380/188Re03/0432.1 (03/04)2.9 (07/04)24 (l.c.)68mIV10/021370/188Re05/0422.5 (05/04)3.1 (06/04)21 (l.c.)50mIV10/0311,110/131I01/0422.1 (01/04)2.2 (03/04)12 (l.c.)68mIV08/0224,090/131I02/05–07/0552.3 (11/04)2.9 (09/05)38 (l.c.)† death, l.c. last contactFig. 2Serial MRI and FET PET images of a 69-year-old man after surgery and radiation therapy of a glioblastoma located in the left occipital lobe during and after two RIT cycles (07/04 and 10/04 with 470 MBq 188Re-TN-mAb). Slightly increased homogeneous FET uptake is evident surrounding the tumour cavity (07/04–12/04). Development of tumour recurrence lateral to the resection cavity is indicated by additional nodular FET uptake as shown in the last scan (03/05). The respective TUmax/BG ratios are given below the PET imagesFig. 3Serial MRI and FET PET scans of a 30-year-old man after surgery and radiation therapy of an anaplastic astrocytoma WHO III located in the right parietal lobe before and after 1 RIT cycle (07/02 with 1870 MBq 131I-TN-mAk). a At baseline and 3 months after therapy, slightly increased homogeneous FET uptake at the cavity borders with additional nodular FET uptake ventral of the cavity indicating recurrence. MRI shows no suspicious contrast enhancement. b After reoperation development of another tumour manifestation developed distant the primary location with focal FET uptake and contrast enhancement on MRI as well. The respective TUmax/BG ratios are given below the PET images
In total, 119 PET scans were performed, 34 in the presence of recurrent tumours and 85 while the patient had a tumour-free status. ROC analyses based on two approaches—(a) including all performed PET scans (Fig. 4a) and (b) considering only the PET scan with the highest individual uptake in each patient during follow-up (n=24) (Fig. 4b)—demonstrated the highest discrimination capacity between patients with tumour recurrence and tumour-free patients at a threshold value of 2.4 for the TUmax/BG ratio.
Fig. 4ROC curves illustrating the diagnostic performance of FET PET when varying the decision thresholds. Analyses were performed twice: for all available PET scans (n=119, including 85 scans performed while patients had a tumour-free status and 34 scans in patients with recurrent tumours) (a) and for only that scan presenting with the highest individual uptake (n=24) (b). The sensitivity and specificity pairs for the threshold values between 2.0 and 2.5 are given in the boxes
Comparison of patients with ratios below and above this threshold using Kaplan-Meier curves for progression-free survival (Fig. 5) demonstrated that survival times were significantly longer (p<0.05) in patients presenting with values below this threshold.
Fig. 5Kaplan-Meier curves showing progression-free survival in patients with ratios below (top) and above (bottom) the suggested optimal threshold value (TUmax/BG=2.4)
Visual analysis using a nodular versus a non-nodular uptake pattern as the criterion to distinguish between tumour recurrence and tumour-free status led to correct detection of recurrence in 32 of 34 scans (sensitivity 94%). In 80 of 85 scans performed in a tumour-free status, no additional nodular uptake pattern was present (specificity 94%). In five scans, uptake appeared somewhat focally accentuated owing to circumscribed folding of the cavity wall, and thus mimicked nodular uptake. Restricting visual analysis only to the one scan per patient presenting with the highest FET uptake resulted in correct detection of tumour recurrence in 16 of 17 patients (sensitivity 94%) and of a tumour-free status in five of seven (specificity 71%). In two of seven tumour-free patients, FET uptake that appeared nodular was misleading for reasons mentioned above.
Discussion
Recent studies on locoregional RIT have demonstrated that local administration of radiolabelled monoclonal antibodies may significantly prolong survival times in patients with malignant gliomas [5–9]. The high locally achieved radiation dose, however, may cause inflammatory infiltrates and radiation necrosis more frequently than do standard treatment modalities, rendering differential diagnosis between benign reactive post-therapeutic effects and tumour recurrence more difficult. In particular, abnormal contrast enhancement in necrotic tissue often mimics tumour recurrence and, therefore, neither MRI nor CT allows reliable distinction between tumour and reactive changes in contrast-enhancing lesions [10–12]. Due to the poor prognosis of patients with glioma, however, knowledge of whether RIT has been successful or not is required so that a decision can be made to re-operate or to change to alternative aggressive treatment modalities when necessary.
So far, to our knowledge only one study has reported on results of functional imaging following RIT of glioma. Using PET with FDG as the metabolic marker, Marriott et al. [32] reported in a limited number of ten patients that a metabolic rim of FDG was observed around the tumour cavity after intracavitary administration of 131I-labelled monoclonal antibodies. Based on their findings they suggested that the development of such a rim may be dose dependent but independent of malignant disease. Histologically, the metabolic rim was associated with an inflammatory infiltrate consisting of a relatively increased number of macrophages and fibroblasts. Furthermore, malignant recurrence was suggested in the event of development of new nodularity in the non-malignant FDG-accumulating rim.
To our knowledge, there have been no previous reports of experience with PET and amino acid tracers as metabolic markers in the special setting of locoregional RIT. A recent study that monitored a limited number of patients with FET PET after another locoregional treatment of glioma, namely convection-enhanced delivery of paclitaxel, suggested that FET PET may be more reliable than MRI in differentiating reactive post-therapeutic changes in stable disease from tumour progression [29]. These results strongly encourage the evaluation of FET PET for monitoring of other forms of locoregional glioma therapy.
This is the first study to investigate the use of an amino acid tracer to monitor the effects of locoregional administration of radiolabelled monoclonal antibodies. Twenty-four patients with malignant gliomas were followed up with serial FET PET scans during and/or after intracavitary RIT. Similar to the results reported by Marriott et al. [32], in all cases, even those considered tumour free, PET demonstrated slight homogeneous FET uptake surrounding the resection cavity, which was considered to be a consequence of therapy. However, the results of in vitro and animal studies on the uptake of FET in soft tissue infection [33] or cerebral radiation injury [34] suggest that FET uptake is probably to be explained by a breakdown in the blood-brain barrier rather than by active uptake in macrophages or inflammatory infiltrates, as in the case of FDG. This is supported by the following four observations: Breakdown of the blood-brain barrier following RIT was documented in all patients by a linear contrast-enhancing rim surrounding the resection cavity on MRI scans. Kaim et al. demonstrated that FET uptake was not increased in activated white blood cells of experimental soft tissue infection [33]. In rats, comparison of tracer accumulation in cryolesions characterised by the absence of inflammatory cells and radiation injury demonstrated that slight FET uptake was most likely due to a disruption of the blood-brain barrier and not additional trapping by macrophages. Uptake in radiation injury has generally been reported to be lower than uptake in tumours, suggesting that FET may be superior to FDG for distinguishing radiation necrosis from tumour recurrence [34].
In general, the homogeneous FET uptake around the resection cavity after RIT was somewhat higher than the unspecific uptake observed in a larger patient group after surgery and conventional external radiation therapy [20]. For these standard treatment modalities, the preliminary threshold value for best differentiation between post-therapeutic effects and tumour recurrence has been considered to be 2.0 for the TUmax/BG ratio, whereas in the present study following RIT the threshold value was determined to be 2.4. The somewhat higher unspecific FET uptake after RIT may be explained by a more severe breakdown of the blood-brain barrier, probably induced by the higher local radiation dose. However, based on the limited experience so far, we were not able to document a relationship between extent and time course of FET uptake with the dose administered.
In addition to these general considerations regarding the rim uptake, the time course of FET uptake in relation to the RIT cycles also has to be taken into account. In the seven patients without clinical signs of tumour recurrence, PET demonstrated slightly increasing values initially, with a peak at up to 18 months after RIT, and stable or even decreasing values during further follow-up. In these patients, FET uptake was homogeneous and the TUmax/BG ratio reached the threshold value of 2.4 in only one patient and then in only one (peak) of nine serial scans. In contrast, in the 17 patients presenting with tumour progression during follow-up, PET showed a more focally configured FET uptake in addition to the rim uptake. Semiquantitative evaluation of the slice with the highest uptake showed either stably increased values (in patients with residual tumour) or increasing values, starting from normal ratios and progressing to pathological ratios(in patients who developed recurrence).
Using the threshold value of 2.4 (as determined by ROC analyses) and regardless of the uptake pattern, FET PET was able to distinguish with high discriminatory power between tumour progression during or after RIT and therapy-induced benign changes: in 21/24 patients there was accurate assessment in all serial PET scans, while in the remaining three patients there was false negative assessment, with TUmax/BG ratios of 2.0, 2.1 and 2.2 respectively. However, in all three cases the nodular configuration of FET uptake led to the correct diagnosis. Even in one patient without focal contrast enhancement on MRI, PET showed focally increased FET uptake clearly indicating tumour regrowth, which was later proven by biopsy. Incidentally, this case supports the hypothesis that tumoural uptake independent of blood-brain barrier disruption is mainly mediated by active transport via the transport system L [35–37]. Visual assessment based solely on the FET uptake pattern seemed to provide slightly more sensitive results than those obtained by the ratio method, but at a lower specificity. Both the TUmax/BG ratio and the configuration of FET uptake should be taken into account in order to differentiate optimally between recurrence and benign post-therapeutic effects. If findings are then still considered equivocal, a shorter time interval between follow-up scans (e.g. 6 weeks) offers another option to achieve reliable diagnostic assessment as early as possible.
Even though it was not the aim of this study to assess the predictive value of FET PET for clinical outcome, FET uptake values following RIT could have been used to compare Kaplan-Meier-overall survival curves of patients with ratios below and above the suggested threshold value (TUmax/BG<2.4). This approach, however, was not followed in our study owing to the heterogeneous patient group (patients with and without residual tumour at baseline, various intervals between initial surgery and radioimmunotherapy, various starting points of FET PET monitoring). Instead, a Kaplan-Meier analysis for progression-free survival following RIT was performed, showing significantly longer progression-free survival in patients in whom the maximal individual uptake was below the suggested threshold value, compared to those presenting with values above this threshold.
One possible limitation of the present study was the lack of histological confirmation in 15/24 patients, and especially in five of the seven patients who were considered tumour free. Histopathological confirmation would have been ethically hard to justify in these patients, but its lack gives rise to the question of possible false negative findings. Nevertheless, the unsuspicious long-term clinical follow-up in the patients in question and the fact that the study population consisted only of patients with high-grade gliomas, and in particular glioblastomas (19/24 patients), strongly support the PET results.
Another possible limitation is that in four of the 24 patients, follow-up with serial FET PET scans did not start until at least 10 months after the end of RIT, with the consequence that some earlier changes in FET uptake following RIT might have been missed. However, since in three of those four patients FET uptake was still increasing during the initial PET scans, followed by a peak and subsequent decrease, it is unlikely that crucial information was missed. Only in one patient in whom RIT had been completed as long as 33 months prior to the beginning of FET PET monitoring were the post-therapeutic phase of increasing FET uptake and its peak probably missed.
Finally, in the present study we abstained from systematically correlating FET PET results with MRI data because the primary goal was to evaluate the value of serial FET PET scans for monitoring the effects of intracavitary RIT. Direct correlations between FET PET and MRI in a similar series of patients following multimodal systemic and/or locoregional treatment have been published recently [38], showing that MRI is insufficient to distinguish between benign side-effects of therapy and tumour recurrence and that FET PET is a powerful tool to improve the differential diagnosis in these patients. Therefore, FET PET might be a method of choice for monitoring locoregional forms of treatment, like RIT, which frequently cause treatment-related inflammatory reactions or tumour necrosis.
Conclusion
This study indicates that FET PET is a sensitive tool for monitoring the effects of high local radiation doses given by intracavitary RIT. Homogeneous, slightly increasing FET uptake around the tumour cavity with a peak up to 18 months after RIT, followed by stable or decreasing FET uptake, is indicative of benign, therapy-related changes. These findings are independent of tumour recurrence and must not be misinterpreted as progressive disease. In contrast, focally increased FET uptake is an early and reliable indicator of tumour progression.
Since both radiation necrosis and active tumour growth can present with clinical deterioration and are often impossible to distinguish by means of structural brain imaging, FET PET may be a powerful tool for planning further patient management. While radiation necrosis may be treated by steroids or, in extensive cases, by debulking surgery, recurrent tumour requires change of ineffective treatment or palliative care only.

intracavitary radioimmunotherapy
malignant glioma
serial fet pet
therapy monitoring