89Zr-Trastuzumab PET/CT Imaging of HER2-Positive Breast Cancer for Predicting Pathological Complete Response after Neoadjuvant Systemic Therapy: A Feasibility Study.

BACKGROUND: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. METHODS: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. RESULTS: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of -48% and -90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was -79% and -94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. CONCLUSIONS: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer.

Systematic approach towards reliable estimation of abdominal aortic aneurysm size by ultrasound imaging and CT.

BACKGROUND: The management of abdominal aortic aneurysm (AAA) is fully dictated by AAA size, but there are no uniform measurement guidelines, and systematic differences exist between ultrasound- and CT-based size estimation. The aim of this study was to devise a uniform ultrasound acquisition and measurement protocol, and to test whether harmonization of ultrasound and CT readings is feasible. METHODS: A literature review was undertaken to evaluate evidence for ultrasound-based measurement of AAA. A protocol for measuring AAA was then developed, and intraobserver and interobserver reproducibility was tested. Finally, agreement between ultrasound readings and CT-based AAA diameters was evaluated. This was an observational study of patients with a small AAA who participated in two pharmaceutical intervention trials. RESULTS: Based on a literature review, an ultrasound acquisition and reading protocol was devised. Evaluation of the protocol showed an intraobserver repeatability of 1.6 mm (2s.d.) and an interobserver intraclass correlation coefficient (ICC) of 0.97. Comparison of protocolled ultrasound readings and local CT readings indicated a good correlation (r = 0.81), but a systematic +4.1-mm difference for CT. Harmonized size readings for ultrasound imaging and CT increased the correlation (r = 0.91) and reduced the systematic difference to +1.8 mm by CT. Interobserver reproducibility of protocolized CT measurements showed an ICC of 0.94 for the inner-to-inner method and 0.96 for the outer-to-outer method. CONCLUSION: The absence of harmonized size acquisition and reading guidelines results in overtreatment and undertreatment of patients with AAA. This can be avoided by the implementation of standardized ultrasound acquisition and a harmonized reading protocol for ultrasound- and CT-based readings.

Accuracy of MRI for treatment response assessment after taxane- and anthracycline-based neoadjuvant chemotherapy in HER2-negative breast cancer.

BACKGROUND: Studies suggest that MRI is an accurate means for assessing tumor size after neoadjuvant chemotherapy (NAC). However, accuracy might be dependent on the receptor status of tumors. MRI accuracy for response assessment after homogenous NAC in a relative large group of patients with stage II/III HER2-negative breast cancer has not been reported before. METHODS: 250 patients from 26 hospitals received NAC (docetaxel, adriamycin and cyclophosphamide) in the context of the NEOZOTAC trial. MRI was done after 3 cycles and post-NAC. Imaging (RECIST 1.1) and pathological (Miller and Payne) responses were recorded. Accuracy measures were calculated and MRI and pathologically assessed tumor sizes were correlated. Tumor size over- and underestimation were quantified. RESULTS: Accuracy of MRI for determining pathological complete response (pCR) was 76%. The ROC-curve of MRI response and pCR had an area under the curve value of 0.63 (95% C.I. 0.52-0.74). The correlation coefficient of MRI and histopathological tumor measurements was 0.46 (p < 0.001). Correlations were different for ER-positive (r = 0.40, p < 0.001) and ER-negative (r = 0.76, p < 0.001) breast tumors. MRI under- and overestimated the tumor size in 47% and 40% of all patients. In cases of substantial tumor size underestimation (>2 cm), surgical margins were more often tumor positive compared to the rest of the patients (33% vs.12%, p = 0.005). CONCLUSION: MRI measurements correlated moderately with tumor size on the surgical specimen. Only in ER-negative breast tumors, MRI tumor sizes correlated sufficiently with residual tumor size on the pathological specimen. Therefore, post-NAC MRI should be interpreted with caution.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. PATIENTS AND METHODS: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. RESULTS: Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. CONCLUSIONS: Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Barrel index of bulky cervical tumours and intrauterine fluid determined by MRI as additional prognostic factors for survival.

OBJECTIVE: to investigate whether morphologic characteristics determined by magnetic resonance imaging (MRI) can discriminate between bulky cervical tumours with a favourable or worse prognosis. MATERIALS AND METHODS: MRI examinations were performed in 24 patients with cervical cancer Stage >or= 1B2. The ratio between tumour width and length (barrel index: BI) and the presence of intrauterine fluid retention were related to survival in a multivariate regression analysis. RESULTS: BI and intracavital fluid were predictors of survival, independent from tumour diameter and other known important factors for survival. A cut-off value of 1.40 for the BI proved to be the best prognostic factor with respect to recurrence and death: the hazard ratios of BI > 1.40 as compared to BI

Intraplacental choriocarcinoma as an unexpected cause of intrauterine death at term.

Intraplacental choriocarcinoma is rare. It can cause fetal death at term by fetomaternal hemorrhage. We present a case of intraplacental choriocarcinoma. After a hydatidiform mole with persistence of throphoblastic disease, the patient delivered a stillborn baby at term. Massive fetomaternal hemorrhage was the unexpected cause of death. Choriocarcinoma was only diagnosed after pathologic revision of the placenta because of persistent high levels of serum hCG (human chorionic gonadotropin). Massive fetomaternal hemorrhage should alert the obstetrician and the pathologist to the possibility of choriocarcinoma arising from the placenta.

Effect of fat digestion on superior mesenteric artery blood flow in humans.

BACKGROUND AND AIM: Intraluminal nutrients stimulate superior mesenteric artery (SMA) blood flow. Of the macronutrients, especially fat affects the magnitude of the SMA blood flow response to a meal. Little is known however on the influence of fat hydrolysis on SMA flow. METHODS: We compared in eight healthy volunteers the SMA flow response (Doppler ultrasonography) to continuous intraduodenal fat perfusion (LCT, 240 kCal h(-1)) during conditions with normal hydrolysis (placebo, control), increased hydrolysis (pancreatic enzyme supplementation; 50 kU lipase) and impaired hydrolysis (orlistat 240 mg). RESULTS: Intraduodenal LCT significantly (P<0.01) increased SMA flow in all experiments over basal. The SMA flow response to fat during pancreatic enzyme supplementation (1.49 +/- 0.1 l min(-1)) was significantly (P<0.05) higher compared with placebo (1.11 +/- 0.16 l min(-1)). Lipase inhibition with orlistat did not significantly affect fat stimulated SMA flow compared with placebo: 0.89 +/- 0.08 l min(-1) versus 1.11 +/- 0.16 l min(-1). CONCLUSIONS: Administration of pancreatic enzymes significantly increases fat stimulated SMA flow. Fat digest products in the intestinal lumen contribute to the regulation of SMA blood flow.

Chronic splanchnic ischaemia.

Chronic splanchnic ischaemia is a relatively unusual clinical entity consisting of pain and/or weight loss and caused by chronic splanchnic disease (i.e. stenosis and/or occlusion of the coeliac and superior mesenteric artery). The occlusive disease is usually caused by atherosclerosis and is in itself not rare in older individuals. Extensive collateral circulation can develop between the three splanchnic arteries and may compensate for the decreased splanchnic perfusion over time. The pathophysiology of chronic splanchnic ischaemia has still not been completely elucidated.A reliable diagnosis of chronic splanchnic ischaemia, based on a proven causal relationship between the occlusive disease and the symptoms, can be very difficult. Traditionally, tests for evaluating the haemodynamic consequences of the vascular stenoses were not available. Important improvements in establishing a more reliable diagnosis have been achieved with duplex ultrasound and magnetic resonance evaluation of the splanchnic circulation. Tonometry is another promising functional test that may prove useful not only for gaining greater insight into the pathophysiology of chronic splanchnic ischaemia but also for the clinical evaluation of this syndrome. The natural history of chronic splanchnic disease suggests that progressive disease may result in acute mesenteric ischaemia. Surgical reconstruction of the coeliac and/or the superior mesenteric artery is the therapeutic standard with excellent short and long-term results. Satisfactory early results using angioplasty with or without stent suggest that this type of intervention may relieve symptoms in selected patients with a higher surgical risk.

MR angiography of the intracranial venous system.

PURPOSE: To compare the effectiveness of different imaging planes at time-of-flight (TOF) magnetic resonance (MR) angiography and phase-contrast MR angiography in the visualization of the normal intracranial venous system. MATERIALS AND METHODS: In 12 healthy volunteers, two-dimensional (2D) TOF MR angiography and three-dimensional (3D) phase-contrast MR angiography were performed in transverse, sagittal, and coronal planes. All data were displayed as maximum intensity projection (MIP) images. Four neuroradiologists assessed the visibility of 28 intracranial venous structures on the MIP images. Statistical analysis was performed by using the Friedman two-way analysis of variance and the Cochran Q test. RESULTS: Visualization of the normal intracranial venous system was better with 3D phase-contrast and coronal 2D TOF MR angiography than with transverse or sagittal 2D TOF MR angiography (P < .05, Friedman test) for each observer and the group of observers. Differences were found between each of the 2D TOF and 3D phase-contrast MR angiographic sequences in the visualization of individual venous structures (Cochran Q test). The kappa values ranged from 0.36 to 0.71, which indicated a moderate to good agreement between observers. CONCLUSION: The normal intracranial venous system is adequately visualized with 3D phase-contrast and coronal 2D TOF MR angiography.

Vascularization of head and neck paragangliomas: comparison of three MR angiographic techniques with digital subtraction angiography.

BACKGROUND AND PURPOSE: MR angiography of the head and neck region has been studied widely, but few studies have been performed concerning the efficacy of MR angiography for the identification of the specific vascular supply of the highly vascular head and neck paragangliomas. In this study, we compared three MR angiography techniques with respect to visualization of branch arteries in the neck and identification of tumor feeders in patients with paragangliomas. METHODS: Fourteen patients with 29 paragangliomas were examined at 1.5 T using 3D phase-contrast (PC), 2D time-of-flight (2D TOF), and multi-slab 3D TOF MR angiography. In the first part of the study, two radiologists independently evaluated the visibility of first-, second-, and third-order branch arteries in the neck. In the second part of the study, the number of feeding arteries for every paraganglioma was determined and compared with digital subtraction angiography (DSA), the standard of reference in this study. RESULTS: Three-dimensional TOF angiography was superior to the other MR angiography techniques studied (P < .05) for depicting branch arteries of the external carotid artery in the neck, but only first- and second-order vessels were reliably shown. DSA showed a total of 78 feeding arteries in the group of patients with 29 paragangliomas, which was superior to what was revealed by all MR angiography techniques studied. More tumor feeders were identified with 3D TOF and 2D TOF angiography than with 3D PC MR angiography (P < .05), with a sensitivity/specificity of 61%/98%, 54%/95%, and 31%/95%, respectively. Sensitivity was lowest for carotid body tumors. CONCLUSION: Compared with intra-arterial DSA, the 3D TOF MR angiography technique was superior to 3D PC and 2D TOF MR angiography for identifying the first- and second-order vessels in the neck. With 3D TOF angiography, more tumor feeders were identified than with the other MR angiography techniques studied. The sensitivity of MR angiography, however, is not high enough to reveal important vascularization. The sensitivity of MR angiography is too low to replace DSA, especially in the presence of carotid body tumors.

Vessel diameter measurements in gadolinium contrast-enhanced three-dimensional MRA of peripheral arteries.

In this study, the possibilities for quantification of vessel diameters of peripheral arteries in gadolinium contrast-enhanced magnetic resonance angiography (Gd CE MRA) were evaluated. Absolute vessel diameter measurements were assessed objectively and semi-automatically in maximum intensity projections (MIPs) of contrast-enhanced T1-weighted 3D spoiled gradient-echo datasets, studied with digital subtraction techniques. In vivo, the complete peripheral arterial bed of six patients was studied, from the aorto-iliac bifurcation down to the distal run-off. By measuring the signal intensity (SI) over the lumen of a vessel in the MIP, an SI-plot was obtained. Next, the vessel boundaries were determined using a threshold algorithm; from these boundary points individual diameter values could be obtained along the trajectory of the vessel. In an in vitro study, an optimal threshold value of 30% of the range of SI-values between the background and the maximal SI in the vessel was obtained for accurate diameter measurement in Gd CE MRA (i.e., full-width 30%-maximum). Furthermore, the relationship between the accuracy of these measurements and the scan resolution was investigated. Accuracy was found to be acceptable (i.e., less than 10% over/underestimation) for vessel sizes covering at least 3 pixels. In six patients, diameters were measured in MIPs of the total datasets (i.e., D(T)) as well as in selective MIPs of the clipped datasets (i.e., D(S)) (n = 209). D(T) and D(S) were statistically significantly correlated (p < 0.01) with a Pearson correlation coefficient rP = 0.98. Measurements in the total MIPs yielded statistically significant (p < 0.01) smaller diameter values compared with measurements in selective MIPs, with a mean difference of 0.15 mm. Diameter values from the selective MIPs of the aorto-iliac arteries were also compared with diameter values measured at corresponding anatomic positions in X-ray angiograms of these patients (i.e., D(x)) (n = 70). D(X) and D(S) were statistically significantly correlated (p < 0.01) with a Pearson correlation coefficient rP = 0.92. Diameters measured in the selective MIPs were smaller than those measured in the X-ray angiograms (mean difference 0.49 mm) and this difference was statistically significant (p < 0.01). In conclusion, diameter values can be evaluated accurately in MIPs of vessels with at least 3 pixels in diameter, using the full-width 30%-maximum criterion.

Magnetic resonance angiography of peripheral vascular disease.

Due to rapid developments in gradient and software technology, magnetic resonance angiography has become a routine clinical tool for imaging of blood vessels in the body. The introduction of contrast-enhanced 3D gradient echo techniques in particular has brought about a turning-point in the application of magnetic resonance angiography in daily clinical practice. This paper presents a brief overview of the various approaches to the application of magnetic resonance angiography for imaging of the peripheral vasculature, not only of the arteries, but also of the veins.

Gadolinium contrast-enhanced three-dimensional MRA of peripheral arteries with multiple bolus injection: scan optimization in vitro and in vivo.

In this study, a scanning protocol was developed to image the arterial bed of the pelvis and both legs along their entire length in patients with peripheral arterial disease, using standard hard- and software. Three adjacent stations are acquired consecutively, with some small overlap; per station; one Gadolinium contrast bolus is administered. The scanning protocol was optimized in an in vitro phantom study. The optimal flip angle was found to be 50 degrees. Also, the optimal scan delay was chosen to be equal to the arrival time of the contrast bolus thereby minimizing artifacts. Three contrast bolus injections showed sufficient enhancement of the vessels after image subtraction. Finally, stenosis quantification by manual caliper was performed by five observers in the MRA images and correlated with the percent diameter reduction determined by quantitative angiography from corresponding X-ray images. The results of the MRA measurements were reproducible and intra- and inter-observer variabilities were statistically non-significant (p = 0.54 and p = 0.12, respectively). Stenosis quantification performed by four observers showed a good correlation with the X-ray derived values (rp > 0.90, p < 0.02); the results from one observer were not significantly correlated. Five patients with proven peripheral disease were investigated with this new MRA scanning protocol. The images were of good quality which allowed adequate clinical evaluation; the original diagnoses obtained from X-ray examinations, were confirmed with MRA. In conclusion, peripheral arterial disease can be evaluated adequately with this MR scanning protocol.

Scan optimization of gadolinium contrast-enhanced three-dimensional MRA of peripheral arteries with multiple bolus injections and in vitro validation of stenosis quantification.

In this study, a T1-weighted three-dimensional (3D) spoiled gradient-echo scanning protocol was developed to image the complete arterial system of the pelvis and both legs along their entire length in patients with peripheral arterial disease. Three adjacent stations were to be acquired consecutively, with some overlap, to image the entire area of interest; per station one gadolinium (Gd) contrast bolus would be administered. In an in vitro phantom study, the scanning protocol was optimized. The optimal flip angle was found to be 50 degrees. Also, the optimal scan delay was chosen to be equal to the arrival time of the contrast bolus, thereby minimizing artifacts. Three contrast bolus injections showed sufficient enhancement of the vessels after image subtraction. Finally, stenosis quantification by manual caliper was performed by five observers in the magnetic resonance angiography (MRA) images and correlated with the percent diameter reduction determined by quantitative angiography from corresponding X-ray images. The MRA measurements were reproducible, and intra- and interobserver variabilities were statistically non-significant (p=0.54 and p=0.12, respectively). Stenosis quantification performed by four observers showed a good correlation with the X-ray-derived values (rp > 0.90, p < 0.02); the results from one observer were not significantly correlated. Five patients with proven peripheral disease were investigated with this new MRA scanning protocol, using standard hardware and software. The images were of good quality, which allowed adequate clinical evaluation; the original diagnoses obtained from X-ray examinations, were confirmed with MRA. In conclusion, peripheral arterial disease can be evaluated adequately with this magnetic resonance scanning protocol.

Stenosis quantification from post-stenotic signal loss in phase-contrast MRA datasets of flow phantoms and renal arteries.

In this study a semi-automated and observer-independent algorithm for quantifying post-stenotic signal loss (PSL) in 3D phase-contrast (PC) magnetic resonance angiography (MRA) of patients with renal artery stenosis is presented. This algorithm was developed on MRA datasets of stenotic phantoms, which were included in a flow circuit with stationary flows. The length and the severity of the PSL (incorporating both length and degree of PSL) in the maximum intensity projections (MIPs) of MRA datasets were proposed for quantifying stenoses. The algorithm was tested in renal arteries of ten patients with renal artery stenosis and seven healthy volunteers. Digital subtraction angiography (DSA) was performed in the patients and served as the gold standard. Stenosis severity showed better correlation with the severity of the PSL than with the length, both for in vitro as in vivo. Spearman correlation coefficients (rS) showed statistically significant correlations between the severity of the PSL and parameters determined by DSA, i.e. percent diameter stenosis (rS = 0.90). The length of the PSL showed no correlation with the diameter stenosis (rS = 0.37).

[Unconventional imaging techniques in inflammatory bowel diseases]. / Niet-conventionele beeldvormende technieken bij inflammatoire darmziekten.

In patients with inflammatory bowel disease (IBD), radiologic examinations are important for diagnosis and treatment. With conventional X-ray examinations, mucosal abnormalities, ulcers and fistulas can be visualised, but no information on the extramural extension of the disease can be obtained. Newer radiologic modalities (ultrasound, CT and MRI) offer new diagnostic possibilities. With ultrasound IBD can be diagnosed with good confidence and it can differentiate between Crohn's disease and ulcerative colitis. CT and MRI are indicated not so much to diagnose the disease but rather to determine the severity and spread of disease activity (transmural and extramural inflammation) and to detect complications such as fistulas and abscesses.

Comparison of inversion-recovery gradient- and spin-echo and fast spin-echo techniques in the detection and characterization of liver lesions.

PURPOSE: To compare respiratory-triggered inversion-recovery (IR) gradient- and spin-echo (GRASE) magnetic resonance (MR) imaging with respiratory-triggered T2-weighted fast spin-echo (SE) imaging in the diagnosis of liver metastases. MATERIALS AND METHODS: In this prospective study, two radiologists independently identified focal hepatic lesions on respiratory-triggered IR GRASE and respiratory-triggered fast SE MR images in 28 consecutive patients with 186 (135 malignant and 51 benign) proved lesions. A combination of findings at surgery, intraoperative ultrasonography (US), and histologic examination served as the standard of reference. Contrast-to-noise ratios (CNRs) were obtained from 86 lesions larger than 10 mm. RESULTS: The sensitivity in the detection of liver metastases was, independent of lesion size and observer, higher for IR GRASE imaging (55%) than for fast SE imaging (44%-50%) (observer 1, P = .014; observer 2, P = .21). Confidence levels with IR GRASE imaging were higher, but not significantly so, than those with fast SE imaging (P < .098). Both observers characterized liver lesions better with IR GRASE than with fast SE imaging (observer 1, P = .04; observer 2, P = .48). The metastasis-liver CNR was significantly higher (P = .012) with IR GRASE imaging. CONCLUSION: The respiratory-triggered IR GRASE sequence is a fast alternative to the respiratory-triggered fast SE sequence in the evaluation of suspected liver metastases.