Anthropogenic gadolinium in the Tone River (Japan): an update showing a 7.7-fold increase from 1996 to 2020.

BACKGROUND: Anthropogenic gadolinium (Gd), originating from Gd-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI), is widely identified in the aquatic environment with concerns about toxicity and accumulation. We aimed to present new data on anthropogenic Gd in the Tone River, which has the largest drainage area in Japan, and then to compare the current data with those obtained in 1996. METHODS: The water samples were collected on August 9-10, 2020, at 15 different locations of the Tone River in Japan. The concentrations of the rare earth elements (REEs) were measured by inductively coupled plasma-mass spectrometry and normalized to Post-Archean Australian Shale to construct shale-normalized REE patterns. The degree of Gd-anomaly was defined as the percentage of anthropogenic Gd to the geogenic background and used to compare the water samples from different locations. Pearson's correlation coefficients were calculated. RESULTS: All the samples displayed positive Gd anomalies. The Gd-anomaly ranged from 121 to 6,545% and displayed a repeating decrease-and-increase trend. The Gd-anomaly showed strong positive correlations to the number of hospitals (r = 0.88; p < 0.001) and their MRI units (r = 0.89; p < 0.001). CONCLUSIONS: Our study revealed notable anomalies of Gd concentrations in river water in Japan, with strong positive correlations to the number of major hospitals and their MRI units. Compared with the previous report in 2000, the Gd-anomaly in Tone River increased from 851% (sampled in 1996) to 6,545%, i.e., 7.7 times, reflecting the increased use of GBCAs in hospitals. RELEVANCE STATEMENT: Notable Gd concentration anomalies in river water in Japan were observed. This result underlines the importance of more extensive research on anthropogenic gadolinium, and investigations of risks to human health as well as the development of effective removal technologies may be necessary. KEY POINTS: • All water samples from Tone River displayed positive Gd anomalies. • The Gd anomalies increased to 7.7 times higher over the past 24 years. • Correlations between Gd values and the number of hospitals and MRI units were observed.

Neutrophil elastase in the development of nephrogenic systemic fibrosis (NSF)-like skin lesion in renal failure mouse model.

Although neutrophil elastase (NE) may play a role in lung fibrosis and liver fibrosis, NE involvement in the development of nephrogenic systemic fibrosis has been unclear. We investigated the involvement of NE in the development of nephrogenic systemic fibrosis-like skin lesions post-injections of linear gadolinium-based contrast agents in renal failure mouse models. Renal failure mouse models were randomly divided into three groups: control group (saline), gadodiamide group, and gadopentetate group. Each solution was intravenously administered three times per week for three weeks. The mice were observed daily for skin lesions. Quantification of skin lesions, infiltrating inflammatory cells, and profibrotic cytokines in the affected skin was performed by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). Blood samples were collected from the facial vein to quantify NE enzymatic activity. The 158Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry (ICP-MS). In the gadodiamide group, the mRNA expression of fibrotic markers was increased in the skin lesions compared to the control group. In the gadopentetate group, only collagen 1α and TGF-ß mRNA expression were higher than in the control group. The expression of CD3+, CD68+, NE cells and the NE activity in the blood serum were significantly higher in the gadodiamide and gadopentetate groups compared to the control group. Gadolinium concentration in the skin of the gadodiamide group was significantly higher than the gadopentetate group, while almost no traces of gadolinium were found in the control group. Although gadopentetate and gadodiamide affected the fibrotic markers in the skin differently, NE may be involved in the development of fibrosis linked to the GBCAs injections in renal failure mouse models.

Immuno-PET imaging for non-invasive assessment of cetuximab accumulation in non-small cell lung cancer.

BACKGROUNDS: Overexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels. METHODS: The NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either 111In- or 64Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting. RESULTS: We found that tumors with high EGFR expression had significantly higher [111In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [111In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [64Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [64Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors. CONCLUSION: Our findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.

Early prediction of triple negative breast cancer response to cisplatin treatment using diffusion-weighted MRI and 18F-FDG-PET.

BACKGROUND: We evaluated the potential of diffusion-weighted MRI (DW-MRI) and 18F-FDG-PET for the early prediction of a triple negative breast cancer (TNBC) response to cisplatin. METHODS: Cisplatin-treated TNBC tumor-bearing mice were categorized as responders or non-responders based on the tumor growth rate. DW-MRI and 18F-FDG-PET were performed before and after treatment (day 0 and days 3 and 7, respectively). The average apparent diffusion coefficient value (ADCmean), the highest standardized uptake value (SUVmax), and the metabolic tumor volume (MTV) were measured. The ratios of each parameter relative to day 0 were calculated [ΔADCmean (day 3) and (day 7), ΔSUVmax (day 3) and (day 7), and ΔMTV (day 3) and (day 7), respectively]. Overall survival rates were compared based on the thresholds determined by these parameters. RESULTS: Both the day 3 and day 7 ratios of ADCmean and MTV showed significant differences between the responder and non-responder groups, whereas the ratios of SUVmax did not. Mice with ΔADCmean (day 3) exceeding the threshold showed a longer overall survival rate. Mice with ΔSUVmax (day 7), ΔMTV (day 3), and ΔMTV (day 7) below the respective thresholds showed a longer overall survival rate. CONCLUSIONS: The ratios of ADCmean, SUVmax, and MTV have the potential to predict the therapeutic response and to screen non-responders in the ultra-early phase following cisplatin treatment in patients with TNBC.

Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model.

OBJECTIVE: To investigate the distribution and clearance of retained gadolinium (Gd) in various parts of the brain after intravenously administering a Gd-based contrast agent (GBCA) in normal and renal failure mouse models. METHODS: Two different mouse models: normal (n = 12) and renal failure (n = 12) were used. Clinical GBCAs (Gd-DTPA-BMA, 5 mmol kg(-1), or Gd-DOTA, 5 mmol kg(-1)) were intravenously administered five times per week for 4 weeks. Both groups were divided into two subgroups based on the time point for sample collection: 3 days (3d) and 45 days (45d) after the last injection. Normal saline (5 ml kg(-1)) was intravenously administered to mice of the control groups in the same manner. Samples of the following parts of the mouse brain were obtained on dissection: olfactory bulb, cerebral cortex, hippocampus, thalamus, mid-brain, cerebellum, pons and medulla. (158)Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry. RESULTS: The olfactory bulb had the highest Gd concentration in both Gd-DTPA-BMA and Gd-DOTA groups. Gd retention was higher in the Gd-DTPA-BMA group than in the Gd-DOTA group (p < 0.01). In the Gd-DTPA-BMA group, Gd retention in the 3d subgroups of normal and renal failure models were similar (p = 0.4). At 45d, Gd in the Gd-DTPA-BMA group was not eliminated from the renal failure model (p = 0.1), while that in the Gd-DOTA group was eliminated from both the normal and renal failure mouse models (p < 0.01). CONCLUSION: Gd distributions in the brain for both groups were similar, regardless of the renal function and GBCA type. The Gd concentration was highest in the olfactory bulb of both groups. In the Gd-DOTA group, Gd was eliminated from the brain in both mouse models, while in the Gd-DTPA-BMA group, Gd clearance was limited. ADVANCES IN KNOWLEDGE: Gd concentration in the brain was not affected by renal function. The clearance of Gd from linear GBCA was limited in both the normal and impaired renal function mouse models.

Impact of Impaired Renal Function on Gadolinium Retention After Administration of Gadolinium-Based Contrast Agents in a Mouse Model.

OBJECTIVES: The aim of this study was to investigate the impact of impaired renal function on gadolinium (Gd) retention in various organs after Gd-based contrast agent injection. MATERIALS AND METHODS: After local animal care and review committee approval, 23 normal mice and 26 with renal failure were divided into 4 treatment groups (Gd-DTPA-BMA, 5 mmol/kg; Gd-DOTA, 5 mmol/kg; GdCl3, 0.02 mmol/kg; and saline, 250 µL). Each agent was intravenously administered on weekdays for 4 weeks. Samples were collected on days 3 (short-term) and 45 (long-term) after the last injection. Gadolinium concentrations were quantified by inductively coupled plasma-mass spectrometry. RESULTS: Three mice with renal failure and 2 normal mice in the GdCl3 group and 1 mouse with renal failure in the Gd-DTPA-BMA group died. In the Gd-DTPA-BMA group, impaired renal function increased short-term Gd retention in the liver, bone, spleen, skin, and kidney (P < 0.01) but did not affect long-term Gd retention. Gd-DTPA-BMA showed higher Gd retention than Gd-DOTA. Although Gd retention in the Gd-DOTA group was generally low, impaired renal function increased only long-term hepatic Gd retention. Hepatic and splenic Gd retentions were significantly higher than other organs' Gd retention in the GdCl3 group (P < 0.01). Renal function did not affect brain Gd retention, regardless of the Gd compound used. CONCLUSIONS: The tendency of Gd retention varied according to the agent, regardless of renal function. Although renal impairment increased short-term Gd retention after Gd-DTPA-BMA administration, long-term Gd retention for Gd-based contrast agents was almost unaffected by renal function, suggesting that the chemical structures of retained Gd may not be consistent and some Gd is slowly eliminated after initially being retained.