Baseline patient, tumor, and MRI characteristics
Primary glioma samples from 69 patients were included (28 glioblastomas, 27 diffuse astrocytomas, and 14 oligodendrogliomas; Table 1). Viable tumor tissue was obtained from all 69 samples, normal brain from 14 samples, and necrosis from 14 glioblastomas. One normal brain sample was excluded since the patient had received three doses of gadopentetate dimeglumine 11 years earlier (without evidence of brain tumor on MRI). This may affect gadolinium deposition in the normal brain and would influence the analyses since at the time of glioma diagnosis the patient received gadoterate meglumine only. Finally, 13 normal brain samples were analyzed.
All glioblastomas showed distinct contrast enhancement whereas in diffuse gliomas the enhancement was more variable. Gadoterate meglumine (Dotarem, Guerbet, Villepinte, France) was used in 60 patients, gadobutrol (Gadovist, Bayer, Whippany, NJ, USA) in two, gadodiamide (Omniscan, GE Healthcare, Chicago, IL, USA) in four, and gadopentetate dimeglumine (Magnevist, Bayer, Whippany, NJ, USA) in three patients, respectively. Linear GBCAs were administered during 2006–2009 and macrocyclic agents 2005–2013. Sixty patients received only one GBCA dose, and nine patients received two to three doses (exclusively gadoterate meglumine) prior to surgery and with evidence of the tumor occurring in the brain MRI. The mean interval between the last GBCA administration and operation was 24 days (range 1–104 days). None of the patients suffered from renal failure.
Gadolinium is detected both in enhancing and non-enhancing gliomas
Gadolinium was detected in 39 out of 69 (57%) tumor samples. Gadolinium retention was most common in glioblastomas, however, without significant difference among diagnoses. In contrast, gadolinium retention associated with contrast enhancement (chi-square p = 0.04, Table 2). Gadolinium was significantly higher in gliomas with noticeable contrast enhancement compared to non-enhancing gliomas (p = 0.02, Fig. 1). However, it should be noted that 7 out of 21 (33%) patients with non-enhancing gliomas showed detectable gadolinium (Fig. 2). Among these, six had received gadoterate meglumine and one gadobutrol, respectively. The routinely used dosage of GBCAs was 0.2 ml/kg. For four patients with one GBCA MRI, the dosage was 0.1 ml/kg. No difference in gadolinium retention was detected with regard to the dose (p = 0.62), GFR value (p = 0.17), or number of GBCA doses administered (p = 0.34; gadoterate meglumine was exclusively used in patients receiving multiple GBCA doses).
Gadolinium retention in gliomas is related to linear GBCAs
As presented in Fig. 3, significantly higher gadolinium concentrations were detected in tumors after administration of linear gadodiamide (median 627 μg/kg, range 319–2624 μg/kg, P25th 322 μg/kg, P75th 2199 μg/kg, n = 4; p = 0.002) and linear gadopentetate dimeglumine (median 349 μg/kg, range 164–3549 μg/kg, n = 3, p = 0.03) when compared with the macrocyclic gadoterate meglumine (median 4.5 μg/kg, range 0–1648 μg/kg, P25th 0 μg/kg, P75th 82 μg/kg, n = 60). No difference in tumor gadolinium was measured between the two linear agents or gadobutrol (range 34–627 μg/kg, n = 2) and other GBCAs. A negative correlation was found between tumor gadolinium concentration and the time interval between MRI and operation (Spearman’s rho = − 0.28, p = 0.02).
For the purpose of linear multivariate regression, GBCA type was analyzed as macrocyclic (gadoterate meglumine and gadobutrol) or linear (gadodiamide and gadopentetate dimeglumine). Linear regression was calculated to predict tumor gadolinium concentration (dependent variable) based on age, sex, tumor contrast enhancement, GBCA type, and MRI–operation interval (independent variables). Thirty one percent of the tumor gadolinium variance could be explained by the predictors (R2 = 0.312). GBCA type (macrocyclic versus linear) was the only significant predictor of tumor gadolinium concentration, which was 1042 μg/kg higher with linear compared with macrocyclic agents (p < 0.001, unstandardized coefficient 1042 μg/kg, 95% CI 628–1457 μg/kg).
Gadolinium retention in normal brain and necrosis is higher after exposure to linear gadodiamide
Gadolinium was detected in 8 out of 13 (62%) samples of histologically normal appearing brain (Table 2) with a significant correlation between gadolinium concentrations in the tumor and normal brain (Spearman’s rho = 0.65; p = 0.016; n = 13). Of these eight patients with gadolinium detected in the normal brain, two had received linear gadodiamide and six macrocyclic gadoterate meglumine, respectively. As shown in Fig. 4, gadolinium concentration in normal brain was significantly higher after exposure to linear gadodiamide (range 361–447 μg/kg, n = 2) compared with macrocyclic gadoterate meglumine (median 13 μg/kg, range 0–403 μg/kg, P25th 0 μg/kg, P75th 32 μg/kg; n = 11; p = 0.04).
Gadolinium retention was also detected in 12 out of 14 (86%) necrotic tissue samples (Table 2) with a significant correlation between gadolinium concentration in the tumor and necrosis (Spearman’s rho = 0.66; p = 0.01; n = 14). Necrosis gadolinium was significantly higher after exposure to linear gadodiamide (median 2852 μg/kg, range 639–15,012 μg/kg, n = 3) compared with macrocyclic gadoterate meglumine (median 118 μg/kg, range 0–1518 μg/kg, P25th 16 μg/kg, P75th 348 μg/kg; n = 9) as presented in Fig. 5 (p = 0.04). No difference in necrosis gadolinium was measured between gadoterate meglumine and gadopentetate dimeglumine (range 1734–1847 μg/kg, n = 2), or the two linear agents.
No significant difference in gadolinium concentrations were detected between tumor and normal brain, or tumor and necrosis, when comparing the concentrations within patients that had either normal brain (n = 13) or necrotic tissue samples (n = 14) available, respectively. Three patients had all three tissue specimens available. No significant difference, however, was detected in gadolinium concentrations between tumor, normal brain, and necrosis within the three patients.