Gerhard Ulrich

Predictive Value of Intratumoral 99mTc-Macroaggregated Albumin Uptake in Patients with Colorectal Liver Metastases Scheduled for Radioembolization with 90Y-Microspheres

90Y radioembolization is a promising therapy for patients with primary and secondary liver malignancies. Pretherapeutic assessment consists of hepatic angiography and 99mTc-macroaggregated albumin (99mTc-MAA) perfusion scintigraphy to estimate the liver-to-lung shunt and exclude extrahepatic 99mTc-MAA deposition. However, the predictive value of intratumoral 99mTc-MAA uptake remains unclear. Methods: One hundred four patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer were treated with 90Y radioembolization between December 2006 and December 2010. All of the patients underwent angiographic assessment and perfusion scintigraphy with 99mTc-MAA before lobar 90Y radioembolization. For inclusion, patients must have undergone pretherapeutic and follow-up MR imaging (6 wk and 3 mo after radioembolization, respectively). The degree of intratumoral 99mTc-MAA uptake was rated, and liver metastases were classified according to changes in tumor diameter on both an individual and a patient basis using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response at both time points, MAA uptake, and catheter position were then statistically analyzed in a linear and generalized linear mixed model at a significance level of 0.05 (P value). Results: Sixty-six patients with a total of 435 colorectal liver metastases (mean number of lesions ± SD, 6.6 ± 2.8; mean lesion size ± SD, 33.8 ± 21.2 mm; lesion size range, 10–154 mm) were included in this analysis. According to the patient-based analysis, 3 patients had partial response, 49 stable disease, and 6 progressive disease after 6 wk. After 3 mo, 5 patients showed partial response, 26 stable disease, and 17 progressive disease. There was no association of patient-based tumor response with overall 99mTc-MAA uptake (P = 0.172) or with catheter position (P = 0.6456). Furthermore, an interaction effect of 99mTc-MAA uptake and catheter position in relation to tumor response was not found (P = 0.512). Moreover, in lesion-based analysis according to RECIST 1.1 there was no association of tumor response with degree of 99mTc-MAA uptake, catheter position, or interaction of 99mTc-MAA uptake and catheter position (P = 0.339, 0.593, and 0.658, respectively). Conclusion: Response to 90Y radioembolization was found to be independent of the degree of 99mTc-MAA uptake. Therefore, therapy should not be withheld from patients with colorectal liver metastases lacking intratumoral 99mTc-MAA accumulation.

Estimation of return-to-sports-time for athletes with stress fracture – an approach combining risk level of fracture site with severity based on imaging

BackgroundThe aim was to compare the return-to-sports-time (RTST) following stress fractures on the basis of site and severity of injury. This retrospective study was set up at a single institution. Diagnosis was confirmed by an interdisciplinary adjudication panel and images were rated in a blinded-read setting.Methods52 athletes (female, n = 30; male, n = 22; mean age, 22.8 years) with stress fracture (SFX) who had undergone at least one examination, either MRI or bone scintigraphy, were included. Magnetic resonance images (MRI) and/or bone scintigraphy (BS) of SFX were classified as either low- or high-grade SFX, according to existing grading systems. For MRI, high-grade SFX was defined as visibility of a fracture line or bone marrow edema in T1-, T2-weighted and short tau inversion recovery (STIR) sequences, with low-grade SFX showing no fracture line and bone marrow edema only in STIR and/or T2-weighted sequences. In BS images, a mild and poorly defined focal tracer uptake represented a low-grade lesion, whereas an intense and sharply marginated uptake marked a high-grade SFX. In addition, all injuries were categorized by location as high- or low-risk stress fractures. RTST was obtained from the clinical records. All patients were treated according to a non-weight-bearing treatment plan and comprehensive follow-up data was complete until full recovery. Two-sided Wilcoxon’s rank sum test was used for group comparisons.ResultsHigh-risk SFX had a mean RTST of 132 days (d) [IQR 64d – 132d] compared to 119d [IQR 50d – 110d] for low-risk sites (p = 0.19). RTST was significantly longer (p = 0.01) in high-grade lesions [mean, 143d; IQR 66d – 134d] than in low-grade [mean, 95d; IQR 42d – 94d]. Analysis of high-risk SFX showed no difference in RTST (p = 0.45) between high- and low-grade [mean, 131d; IQR 72d – 123d vs. mean, 135d; IQR 63d – 132d]. In contrast, the difference was significant for low-risk SFX (p = 0.005) [low-grade; mean, 61d; IQR 35d – 78d vs. high-grade; mean, 153d; IQR 64d – 164d].ConclusionFor SFX at low-risk sites, the significant difference in RTST between low- and high-grade lesions allows more accurate estimation of RTST by this approach. Both location of the injury and severity determined by imaging should therefore be considered for prediction of RTST.

Blinded-read of bone scintigraphy: the impact on diagnosis and healing time for stress injuries with emphasis on the foot.

Aim: This study evaluated the use of bone scintigraphy (BS) for the diagnosis of stress fractures in athletes and its validity for the prediction of healing time, with a focus on foot injuries. Methods: In our retrospective study, 84 athletes with a total of 93 suspected stress fractures (foot, n = 66; others, n = 27) were included. A blinded-read of BS was performed by 3 observers. The standard of reference was established by an interdisciplinary truth-panel using all imaging data (scintigraphic, radiographic, and magnetic resonance imaging) and follow-up data (>12 month). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosing stress fractures were calculated. Stress injuries were rated according to a 5-point grading score (0–4) and associated to the healing time. Results: For the diagnosis of stress injuries (n = 50/93), mean sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 97.3%, 67.4%, 77.7%, 95.6%, and 83.5%, respectively. Interobserver analysis showed a high agreement between all 3 readers (mean &kgr; = 0.83). In univariate analysis healing time of grade 3 to 4 stress injuries was significantly higher (median, 87 days; interquartile range, 69–132 days) compared with grade 1 to 2 lesions (median, 63 days; interquartile range, 43–95 days; P = 0.0067). Moreover, healing time of scintigraphic high grade stress injuries was significantly longer in a general linear model with adjustment for cofactors (grade, 3–4 vs. 1–2; P = 0.033). Conclusions: BS is a sensitive and reliable method for the diagnosis of stress injuries. In addition, the simplified classification for mild and severe stress injuries allows an estimation of healing time.

Safety of Repeated Radioembolizations in Patients with Advanced Primary and Secondary Liver Tumors and Progressive Disease After First Selective Internal Radiotherapy

The purpose of this study was to assess the safety of repeated 90Y radioembolization with resin microspheres in patients with extensive primary and secondary liver tumors after failure of first radioembolization. Methods: Between 2007 and 2011, 21 patients (12 women, 9 men; mean age, 61.0 y) with nonresectable advanced liver tumors (breast cancer liver metastases, n = 7; colorectal liver metastases, n = 5; hepatocellular carcinoma, n = 8; cholangiocellular carcinoma, n = 1) were repeatedly treated by radioembolization. Safety was the primary endpoint. Whole-liver treatment was achieved with sequential treatment sessions in most patients, with selective embolization of the left and right liver lobes within 6 wk. Toxicity was documented prospectively and according to Common Terminology Criteria for Adverse Events 4.0 criteria based on laboratory parameters; magnetic-resonance tomography; and clinical examinations 3 d, 6 wk, and every 3 mo after selective internal radiotherapy (SIRT). Metric variables were evaluated using the Student t test. Overall survival was assessed by Kaplan–Meier statistics. Results: Patients received an average of 1.6 whole-liver treatments performed in 3.0 unilobar radioembolizations (liver lobes sequentially). The mean total activity administered was 2.57 GBq. No radioembolization-induced liver disease was observed in any of the patients. Three patients showed reversible grade III to IV toxicities according to laboratory values, which returned to pretreatment levels after 6 wk. In 1 patient, a treatment-related duodenal ulcer occurred. Median overall survival was 18 mo after first radioembolization. Conclusion: In advanced liver tumors, repeated whole-liver treatments with 90Y radioembolization can be performed with an acceptable toxicity profile.

Effectiveness of Repeat Angiographic Assessment in Patients Designated for Radioembolization Using Yttrium-90 Microspheres With Initial Extrahepatic Accumulation of Technitium-99m Macroaggregated Albumin: A Single Center’s Experience

PurposeTo evaluate the efficacy of a workflow consisting of repeat assessment in patients planned for yttrium-90 (90Y) radioembolization in case of nontarget visceral technetium-99m (99mTc)-macroaggregated albumin (MAA) accumulation despite initial prophylactic coil embolization of nonhepatic arteries.Materials and MethodsIn 341 patients with primary and secondary liver cancer, pretreatment hepatic angiograms, as well as single-photon emission computed tomography coregistered with magnetic resonance imaging scans, were obtained. Extrahepatic tracer deposition was identified in 33 patients (9.7%) necessitating repeat assessment. Images were reviewed to correlate the site of MAA accumulation with causative gastrointestinal vessels, and repeat angiograms served as reference standard.ResultsAt repeat angiography, the source of extrahepatic flow was identified and eliminated in 31 of 33 patients (93.9%). In 20 patients (60.6%), successful embolization of nontarget vessels was achieved, in 13 patients (39.4%), MAA was administered more distally. Afterward, extrahepatic MAA deposition was eliminated in 30 patients (90.9%).ConclusionThe algorithm of repeat assessment in case of extrahepatic MAA accumulation has proven highly effective to eliminate extrahepatic shunting, thus decreasing the risk of postradioembolization complications due to inadvertent visceral microsphere deposition.

Intrahepatic Activity Distribution in Radioembolization with Yttrium-90-Labeled Resin Microspheres Using the Body Surface Area Method--A Less than Perfect Model.

PURPOSE To retrospectively assess the influence of the parameters of the body surface area (BSA) method in hepatic radioembolization using yttrium-90-labeled microspheres on the determination of the prescribed activity. MATERIALS AND METHODS Data from 283 consecutive patients treated with radioembolization (BSA method) were included. For interindividual comparisons, activity concentrations (ACs; MBq/mL) were calculated for each liver. The impact of the BSA method parameters was assessed by analysis of variance and pairwise t test with Bonferroni-Holm correction. RESULTS Prescribed activity was 1.01-2.71 GBq, with BSA, liver volume (LV), tumor burden, and the liver-lung shunt reduction factor (LLS RF) being significant contributing factors to the AC (all P < .0001, analysis of variance). BSA and LV correlated only moderately (ρ = 0.46, P < .0001). Compared with base activity defined by the BSA (median = 1.67 GBq; range, 1.20-2.32 GBq), the activity contribution of tumor burden was small (median = 150 MBq; range, 3-800 MBq). Resulting activities were reduced according to LLS RF by 20% in 12.4% and by 40% in 3.5% of patients. AC was significantly (up to 56%) lower in association with larger LV than in small LV (LV < 1,500 mL vs ≥ 2,500 mL, P < .0001). CONCLUSIONS In the BSA model, BSA and LV showed only a moderate correlation, resulting in a significantly lower AC in patients with larger livers. Tumor burden percentage contributed little to the prescribed activity because the BSA model did not account for actual LVs and tumor volumes. These inaccuracies may potentially result in underdosage in patients with larger livers, especially if further LLS RF needs to be applied.

Quantification in 68Ga-DOTA(0)-Phe(1)-Tyr(3)-Octreotide Positron Emission Tomography/Computed Tomography: Can We Be Impartial about Partial Volume Effects?

Aim: In combined positron emission tomography/computed tomography (PET/CT) of neuroendocrine neoplasms using 68Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide (68Ga-DOTATOC), partial volume effects (PVEs) may occur in smaller lesions. This study determined the lesional cutoff size for the occurrence of PVEs in a clinical setting. Methods: Retrospective assessment of 51 PET/CT examinations (16-slice PET/CT device) for malignant PET foci was carried out. In all foci, the maximal standardized uptake value (SUVmax) and maximal lesion diameter on axial CT was documented. Determined SUVmax and lesional sizes were correlated via LOESS regression. In the resulting curve, the cutoff point for SUVmax size dependency was determined visually and mathematically using 2 approximating straight lines. Results: In 45 patients, 313 of 413 PET foci found were malignant, measurable on CT and had a roughly spherical geometry (SUVmax: 2.5-103.3, mean ± SD 20.5 ± 15.18; CT diameter: 5-103 mm, mean ± SD 21.8 ± 13.1 mm). The cutoff lesional size for the occurrence of PVEs was 20.4 mm by the mathematical approach and 25 mm by visual assessment. Conclusion: In 68Ga-DOTATOC imaging, the clinical lesional size threshold is far larger than expected from systemic resolution only. Thus, tracer uptake quantification is only acceptable in sufficiently large lesions.

PET imaging with 11C-MDG, but not 18F-FDG, for proof of pharmacology of a sodium-dependent glucose cotransporter 2 inhibitor Ipragliflozin

lations based on 99mTc-MAA imaging, as reported with HCC,. . . should be seen critically.” This statement about HCC cannot be based on a study dealing with a different pathology and a different kind of microsphere. Metastases and HCC are different types of tumors (more peripheral vascularization in HCC and a higher proportion of small lesions in metastases). Results observed with one type of lesion cannot be extrapolated to the other. Ulrich et al. extend their conclusions from results obtained with resin spheres (SIR-Spheres) to glass spheres (TheraSphere; BTG), as if the two medical devices were identical. This is absolutely not the case from the dosimetric and biologic point of view (9). Activity per sphere is 50 times lower for the resin spheres than for the glass ones, requiring a 50 times higher number of particles to give the same mean absorbed dose, with a consequent increased real embolic effect. Because of this tremendous difference between the number of injected particles, we cannot agree about extrapolating results concerning the predictive value of 99mTc-MAA scintigraphy from resin to glass microspheres. The evidence on HCC treatment provided by the teams of Rennes (10) and Milan (2), both of which used glass spheres, in contradiction to what is reported by Ulrich et al., was not discussed adequately. In the first study (mean lesion size of 7.1 cm), 99mTc-MAA SPECT/CT was predictive of response with an accuracy of 90% (10). The lesion-absorbed dose was the only parameter associated not only with response but also with overall survival at multivariate analysis (10). Also, the second study found a dose–response relationship in HCC (2). Mean tumoral absorbed dose significantly correlated with the EASL response (Spearman r 5 0.60, P , 0.001). In conclusion, when reporting on the predictive value of 99mTcMAA scintigraphy in SIRT, one should pay attention to the type of microspheres, the quantification method for estimating the 99mTcMAA degree of perfusion, dosimetry issues, tumor type, lesion size, and the method of response assessment. At present, there is confirmed evidence that 99mTc-MAA SPECT–based dosimetry is predictive of response in HCC when glass microspheres are used. Published results with resin microspheres, especially in metastases, require additional studies to assess the predictive power of 99mTc-MAA scintigraphy. Conclusions from a methodologically weak study about the lack of predictive value of 99mTc-MAA uptake in liver metastases treated with resin microspheres should not be extrapolated to HCC treated with glass microspheres.

Pharmacokinetics of 99mTc-MAA- and 99mTc-HSA-Microspheres Used in Preradioembolization Dosimetry: Influence on the Liver–Lung Shunt

Perfusion scintigraphy using 99mTc-labeled albumin aggregates is mandatory before hepatic radioembolization with 90Y-microspheres. As part of a prospective trial, the intrahepatic and intrapulmonary stability of 2 albumin compounds, 99mTc-MAA (macroaggregated serum albumin [MAA]) and 99mTc-HSA (human serum albumin [HSA]), was assessed. Methods: In 24 patients with metastatic colorectal cancer, biodistribution (liver, lung) and liver–lung shunt (LLS) of both tracers (12 patients each) were assessed by sequential planar scintigraphy (1, 5, and 24 h after injection). Results: Liver uptake of both albumin compounds decreased differently. Although initial LLSs at 1 h after injection were similar in both groups, MAA-LLS increased significantly from 1 (3.9%) to 5 h (7.7%) and 24 h (9.9%) after injection, respectively. HSA-LLS did not change significantly (1 to 5 h), indicating a steady state of pulmonary and intrahepatic degradation. Conclusion: Compared with 99mTc-MAA-microspheres, 99mTc-HSA-microspheres are likely more resistant to degradation over time, allowing a reliable LLS determination even at later time points.

Significance of a Single-Time-Point Somatostatin Receptor SPECT/Multiphase CT Protocol in the Diagnostic Work-up of Gastroenteropancreatic Neuroendocrine Neoplasms

This prospective study compared a 1-d SPECT/CT protocol with the commonly used 3-d protocol for somatostatin receptor scintigraphy in patients with gastroenteropancreatic neuroendocrine neoplasms. Additionally, the influence of SPECT/CT on patient management was evaluated. Methods: From October 2011 to October 2012, all gastroenteropancreatic neuroendocrine neoplasm patients undergoing restaging with somatostatin receptor scintigraphy on a modern SPECT/CT device were enrolled in this study. The protocol consisted of planar imaging at 4, 24, and 48 h; low-dose SPECT/CT at 24 and 48 h; diagnostic CT at 24 h using a triple-phase delay after administration of contrast; and diagnostic SPECT/CT at 24 h. All components of the imaging data were reassessed by 3 masked interpreters. The results were compared with a reference standard based on all clinical, imaging, and histopathology follow-up data available (follow-up range, 24–36 mo; mean, 29.9 mo). The reference standard was defined by a study-specific interdisciplinary tumor board that also reassessed treatment decisions. Results: Thirty-one patients were eligible for analysis (18 men and 13 women; mean age, 60.4 y). Ten had no imaging signs of disease and remained disease-free during follow-up. Twenty-one had persistent or recurrent disease (82 lesions: 24 in the liver, 21 in the lymph nodes, 16 in bone, 12 in the pancreas, and 9 in other locations). The respective lesion detection rates for interpreters 1, 2, and 3 were 51.9%, 49.4%, and 71.6% for low-dose SPECT/CT at 24 h; 51.9%, 55.6%, and 67.9% for low-dose SPECT/CT at 48 h; 63.0%, 70.4%, and 85.2% for diagnostic CT; and 77.8%, 84.0%, and 88.9% for diagnostic SPECT/CT. Interobserver agreement was moderate for diagnostic SPECT/CT (κ = 0.44), diagnostic CT (κ = 0.43), low-dose SPECT/CT at 48 h (κ = 0.61), and low-dose SPECT/CT at 24 h (κ = 0.55). For planar imaging, interobserver agreement was fair after 48 h (κ = 0.36) and 24 h (κ = 0.38) and moderate after 4 h (κ = 0.42). Every lesion detectable on planar imaging or low-dose SPECT/CT was also detectable on diagnostic SPECT/CT. The CT and SPECT components of diagnostic SPECT/CT strongly complemented each other, as 34 of 82 lesions (41.4%) were detected on only the CT component or only the SPECT component. Therapeutic management was influenced by the diagnostic SPECT/CT interpretation in 8 of 31 patients (25.8%). Conclusion: The highest detection rates were achieved by diagnostic SPECT/CT. Thus, a more patient-friendly 1-d protocol is feasible. Furthermore, multiphase SPECT/CT affected management in about a quarter of patients.