Introduction
Stereotactic radiosurgery (SRS) is an effective localized therapy for patients with a limited number of brain metastases and SRS alone results in similar overall survival but with better neurocognitive outcomes than SRS and whole-brain radiotherapy (WBRT) [1–3]. With high precision and sharp dose gradients, SRS permits the application of ablative doses to brain metastases while sparing the surrounding peritumoral tissue. In the context of prolonged survival due to new systemic therapies, SRS can provide the possibility for repeated treatments of sequentially diagnosed brain metastases [4–6]. With extended survival, long term local tumor control gains additional importance. Thus, early markers of response to SRS would be desirable to allow physicians to individually adapt the prescription dose, the dose distribution (e. g., by applying a higher marginal dose or a higher central dose) or the fractionation scheme (e. g., by switching to a fractionated scheme that would allow for re-oxygenation) for (further) radiation treatments [7].
To date, response to SRS is assessed by serial magnetic resonance imaging (MRI), yet early evaluation of changes in size for response prediction has shown mixed results [8–11]. Various additional MRI techniques can be utilized to distinguish progression of brain metastases from pseudo-progression or radionecrosis [12–14].
With 23Na MRI derived sodium-weighted signal, changes of tissue sodium concentration (TSC), originating from changes in intracellular sodium concentration or extracellular volume fraction, can be detected [15–17]. While TSC has previously been shown to be elevated in malignant brain tumors compared to healthy brain tissue, treatment-induced changes of TSC in brain metastases or vestibular schwannoma after SRS have only recently been published [18–21]. As SRS affects brain metastases as well as the peritumoral tissue, 23Na MRI assessment of peritumoral tissue could provide early information regarding radiation dose effects and, together with TSC of brain metastases, could serve as marker for response to radiotherapy. We conducted a study to analyze the longitudinal changes of TSC in the peritumoral tissue of brain metastases, measured with 23Na MRI before and after SRS.
Methods
A prospective study was conducted to investigate early tissue response to SRS. The study protocol was approved by the institutional review board (Ethikkommission II, Heidelberg University, Mannheim Medical Faculty, approval no. 2019–630 N-MA). Written informed consent was obtained from all patients. Written consent was checked and confirmed by the department’s clinical trials unit. In the recruitment period between 03 June 2019 and 29 May 2020, 23Na MRI scans were acquired from 12 patients with one or more previously untreated brain metastases stemming from a known primary tumor that were scheduled to be treated with SRS. For study inclusion, the volume of at least one brain metastasis was required to be ≥ 64 mm3 because of the nominal resolution of the 23Na MRI being 4x4x4 mm3.
Data acquisition
23Na MRI scans were scheduled at three different time points:
1. 2 days pre-SRS (baseline, T = SRS– 2 days): 23Na MRI protocol + 1H MRI routine protocol
2. 5 days post-SRS (T = SRS + 5 days): 23Na MRI protocol
3. 40 days post-SRS (T = SRS + 40 days): 23Na MRI protocol + 1H MRI routine protocol
Scan (I) and (III) were synchronized with routine 1H MRI acquisitions required for SRS planning or post-treatment observations. An additional appointment was scheduled for scan (II). After completion of scan (III), patients underwent follow-up with quarterly physical exams and routine MRI scans. Routine follow-up MRI scans were assessed according to RANO-BM criteria [8].
Data acquisition was performed with the 3T Magnetom Trio (Siemens Healthineers, Erlangen, Germany) and a dual-tuned transmit-receive 1Tx/1Rx 1H/23Na birdcage head coil (Rapid Biomedical, Rimpar, Germany). The MRI protocol included the 23Na MRI and a post-contrast 1H T1w MRI. The 23Na MRI was acquired after the administration of contrast agent, which has been shown to have no significant impact on the following TSC quantification [22]. A 3D radial density-adapted sequence was employed [23] using 9,000 spokes with 384 data points each, resulting in a measurement time of TA = 15 min. The relatively long repetition time of TR = 100 ms allowed minimization of T1-weighting effects and the short echo time of TE = 0.4 ms reduced T2*-weighting effects. Nominal image resolution was 4x4x4 mm3 but a zero-filling factor of 2 was introduced during image reconstruction, generating an apparent resolution of 2x2x2 mm3. Image reconstruction was performed in MATLAB 2018a (The MathWork Inc, Natick, MA, USA), using a regridding algorithm in k-space and a Hanning filter with the width of 4. The 1H routine MRI were acquired with a 12 channel 1H head coil, and the protocol included a T1w, T2w, and a contrast-enhanced (Dotarem, 0.2 ml/kg body weight) T1w 3D magnetization prepared rapid gradient-echo sequence (MPRAGE).
SRS treatment
All patients were treated according to institutional standards with the Leksell Gamma Knife Icon (Elekta AB, Stockholm, Sweden). Segmentation, treatment planning and optimization was conducted with Leksell GammaPlan (Elekta AB, Stockholm, Sweden). Brain metastases were segmented using the contrast-enhanced MPRAGE image acquired at time point (I) as gross tumor volume (GTV). The planning target volume (PTV) was either identical to the GTV (frame fixation system) or an additional margin of 1 mm was added to the GTV to build the PTV (thermoplastic mask fixation). All patients were then treated with a single dose ranging from 16 Gy to 22 Gy prescribed to the 50% isodose line encompassing the PTV.
TSC quantification
Additionally to the segmentation of brain metastases, two cylindrical regions (radius: 5 mm, height: 10 mm) within each patient’s healthy-appearing white matter (healthy ROIs, HR) were defined by a radiation oncologist. Isodose lines for each SRS were calculated with GammaPlan and transformed into DICOM structures. All ROIs were then exported from GammaPlan as DICOM RT files.
The acquired and reconstructed 23Na MRI were co-registered to the contrast-enhanced 1H MPRAGE, which had been used for SRS planning with the aim of being able to transfer the ROIs (GTV, isodose lines and HR) to the 23Na MRI. Therefore, all available 23Na MR images of each patient were co-registered to the same MPRAGE from scan (I). Co-registration was performed with the statistical parametric mapping software SPM12 (Wellcome Trust Centre for Neuroimaging, London, UK). Furthermore, automatic image segmentation into WM, GM, and CSF was performed for being able to exclusively evaluate WM and GM regions with no CSF impingement. Automatic image segmentation was also performed with SPM12.
Quantification was performed by normalization to the signal intensity (SI) within the patients’ left vitreous humor (VH). Three-dimensional ROIs were manually segmented within each patient’s MPRAGE, which was then transferable to all three 23Na MRI because of the image co-registration. The image’s SI was normalized based on SI within that ROI. TSC concentration within the VH was assumed to be constant at 145 mM, equivalent to the extra-cellular 23Na concentration [24, 25], and similar to the findings of Kokavec et al. [26]. A correction of the T1-weighting within the VH was introduced based on an estimated T1 relaxation time of the VH with T1(VH) = 50 ms as was previously suggested by Wenz et al. [27] because similar relaxation times were assumed in VH and CSF. The TSC-map was then calculated by:
DICOM RT structure files were imported into MATLAB with the Computational Environment for Radiological Research (CERR) [28]. It allowed to identify the irradiated and segmented regions from Leksell GammaPlan and enabled evaluation within MATLAB of those regions on the 23Na MRI.
TSC was measured within GTV, HR and the isodose areas of D = 2, 3, 4, 6, 8, 10, 12, and 18 Gy on all 23Na MRI scans of each patient. An isodose area was defined as the area enclosed by the corresponding isodose line with subtraction of the area enclosed by the preceding isodose line. The HR were evaluated to compare the TSC development within the irradiated regions to non-irradiated, healthy-appearing tissue of the same patient for each scan (I, II, and III). The different isodose areas were evaluated to investigate the effect of radiation on healthy tissue. Potential CSF regions within all ROIs were subtracted as described above.
Statistical analysis
Mean TSC within brain metastases, HR, and within all isodose areas was compared between measurements at time points (I), (II), and (III). Differences were tested for statistical significance using the paired student t-test, and p < 0.05 was considered significant. The student t-test was applicable as the Kolmogorov-Smirnov test showed normal distribution.
The Pearson correlation test was used to evaluate a potential correlation between the radiation doses D and the mean TSC within the corresponding isodose area. If not otherwise indicated, values are reported with their mean ± standard deviation.
Results
Twelve patients with a total of 14 brain metastases were evaluated. Mean dose of SRS was 21.4 ± 1.7 Gy and 2 patients (2 brain metastases) were treated with a frame fixation. Out of those, 9 patients (11 brain metastases) underwent all scheduled scans, 2 patients (2 brain metastases) only underwent scan (I) and (II) and one patient (1 brain metastasis) only underwent scan (I) successfully. Median follow up with serial MRI was 13.2 ± 8.4 months. Two patients showed local progression of treated brain metastases (defined as progressive lesion within or overlapping with the PTV). Patient characteristics including histology of the primary are presented in Table 1.
[Figure omitted. See PDF.]
(BM: brain metastases).
One representative transverse slice of the MPRAGE and of the three 23Na MRI of one patient with the GTV, and the isodose line regions being visualized within the MPRAGE are shown in Fig 1.
[Figure omitted. See PDF.]
One representative transverse slice of one patient’s MPRAGE and the co-registered 23Na at all three measurements: scan (I) (t = SRS– 2 days), scan (II) (t = SRS + 5 days), and scan (III) (t = SRS + 40 days). The isodose areas and the two GTV are being visualized within the MPRAGE as color-coded regions.
The mean TSC within all Gross Tumor Volumes (GTV), Healthy ROIs (HR), and the isodose areas of D = 2, 3, 4, 6, 8, 10, 12, 18 at all three scans (I, II, and III) are listed in Table 2.
[Figure omitted. See PDF.]
Statistical significance is indicated by ‘*’. (BM: brain metastases).
Mean TSC in all HR was 45 ± 5 mM. 45 ± 5 mM, and 44 ± 5 mM at scan (I), (II), (III), respectively. There was no statistically significant difference between any of the three scans (all p > 0.7).
Mean TSC in HR was significantly lower than mean TSC in GTV, at all three scans (all p<0.0001). Mean intra-patient TSC differences in the HR was 2 ± 2 mM between all three scans.
In all evaluated GTV, at baseline, scan (I), mean TSC was 61 ± 10 mM, which evolved to 68 ± 9 mM (+ 11%) at scan (II) and 58 ± 9 mM (- 5% compared to baseline) at scan (III). Differences between scan (I) and scan (III) were not statistically significant (p = 0.27) whereas differences between scan (II) and both other scans were statistically significant (p = 0.0076 and p = 0.0214, respectively).
For the GTV of five brain metastases deriving from non-small cell lung carcinoma (NSCLC), mean TSC was 70 ± 5 mM at scan (I), 76 ± 6 mM at scan (II), and 63 ± 6 mM at scan (III). The GTV of the three brain metastases stemming from mammary carcinoma showed a mean TSC of 54 ± 6 mM at scan (I), 58 ± 4 mM at scan (II), and 48 ± 5 mM at scan (III).
The two progressive brain metastases showed mean TSC values of 50 ± 3 mM (primary tumor: soft tissue sarcoma) and 48 ± 2 mM (primary tumor: mammary carcinoma) at scan (I), 53 ± 5 mM and 53 ± 3 mM at scan (II), and 71 ± 5 mM and 50 ± 3 mM at scan (III), respectively.
Mean TSC in GTV and HR at all three scans are depicted as boxplots of the stable brain metastases and of the progressive brain metastases in Fig 2.
[Figure omitted. See PDF.]
Boxplot of the mean TSC within the GTV (blue), and the HR (red) at all three measurements: scan (I) (t = SRS– 2 days), scan (II) (t = SRS + 5 days), and scan (III) (t = SRS + 40 days). The middle line in the box depicts the median value and the boxes’ top and bottom edges the 25th and 75th percentiles of the data, respectively. The whiskers extend to the most extreme data points not considering outliers which are depicted by “+”. The top figure depicts TSC evolution for stable brain metastases and the two bottom figures depict the TSC evolution of the two progressive brain metastases (left: soft tissue sarcoma, right: mammary carcinoma). (BM: brain metastases).
The mean TSC within the isodose areas of D = 2, 3, 4, 6, 8, 10, 12, 18 Gy was lower at baseline, scan (I), compared to measurement at scan (II) for all isodose areas and differences were significant for isodose areas D = 18 to 8 Gy but not for isodose areas D = 6 to 2 Gy. Comparing mean TSC within the isodose areas between scan (I) and scan (III), TSC was higher at baseline within all isodose areas and differences were significant for D = 18 to 3 Gy but not for D = 2 Gy. Comparing mean TSC within the isodose areas between measurements at scan (II) and (III), TSC was higher at scan (II) for all isodose areas and differences were also significant for D = 18 to 3 Gy but not for D = 2 Gy. The respective tendencies and corresponding p-values are given in Table 2.
Fig 3 depicts boxplots of the mean TSC within the isodose line D = 2, 10, and 18 Gy at all three measurements as boxplots.
[Figure omitted. See PDF.]
Boxplot of the mean TSC of all stable brain metastases within the isodose areas D = 18 Gy (blue), D = 10 Gy (red) and D = 2 Gy (yellow) at all three measurements: scan (I) (t = SRS– 2 days), scan (II) (t = SRS + 5 days), and scan (III) (t = SRS + 40 days). The middle line in the box depicts the median value and the boxes’ top and bottom edges represent the 25th and 75th percentiles of the data, respectively. The whiskers extend to the most extreme data points.
Mean TSC evolution within the isodose areas and their ratio between each other at all three scans (I, II, and III) are depicted in Fig 4.
[Figure omitted. See PDF.]
Plot of the mean TSC over the observed isodose areas at all three measurements: scan (I) in blue (t = SRS– 2 days), scan (II) in red (t = SRS + 5 days), and scan (III) in yellow (t = SRS + 40 days). The figure shows the TSC evolution separately for patients with stable brain metastases either from NSCLC or from any other primary. The bottom plot shows the TSC evolution of both patients with progressive brain metastases. Here, the patient with a BM from soft tissue sarcoma is depicted with triangles and the patient with a BM from mammary carcinoma is depicted with pentagrams. (BM: brain metastases).
No significant differences between patients treated with frame fixation compared to those treated with mask fixation were detected in baseline TSC or TSC evolution within the GTV or the isodose areas.
The Pearson correlation test showed a significant, positive correlation between the radiation dose D and the mean TSC within the corresponding isodose area at all three scans. Correlation between D and mean TSC was r = 0.92 (p = 0.0011) at baseline scan (I), r = 0.96 (p = 0.0001) 5 days after SRS at scan (II), and r = 0.86 (p = 0.0061) 40 days after SRS at scan (III).
Discussion
The aim of our study was to evaluate the feasibility of longitudinal 23Na MRI to reveal early changes of peritumoral TSC in addition to changes of TSC in brain metastases after SRS. To our knowledge, this is the first prospective investigation with 23Na MRI to evaluate radiation response in the peritumoral tissue of brain metastases. Our findings demonstrate changes of TSC in the peritumoral tissue following SRS, suggesting that 23Na MRI is sensitive to treatment-related effects, not only within brain metastases but also within the peritumoral tissue.
Altered tissue sodium concentration in brain metastases and peritumoral tissue
TSC in tumors depends on intra- and extracellular sodium concentration and the respective relative volumes. Alterations are believed to originate from accelerated cell division, tumor neovascularization and an increased interstitial space [29–34]. While those compartments affect TSC within brain metastases to various degrees, the peritumoral tissue of untreated brain metastases is primarily subjected to sodium-rich vasogenic edema, elevating TSC in the peritumoral tissue of brain metastases as well as malignant brain tumors [18, 19, 35]. Being caused by leakage of tumor vessels, it is unclear whether the extend of edema volume is more associated with vessel density or vessel disfunction in brain metastases. Yet, vessel density in brain metastases as well as edema volume has been shown to differ depending on the primary histology [33, 36, 37].
SRS-induced changes of tissue sodium concentration
For comparison, we evaluated TSC in healthy-appearing brain tissue that was in line with normal values (between 30–56 mM) for all patients during all scans [38–40]. A very low TSC difference of 2 ± 2 mM was observed in the healthy-appearing white matter, indicating high quantification stability.
Correlating with previously reported data on brain metastases and malignant brain tumors, mean TSC in GTV was elevated compared to healthy-appearing brain tissue with a further rise in mean TSC shortly after SRS and a subsequent decline below initial levels 40 days after SRS [19, 41]. Reflecting radiation-induced changes, the TSC increase within the GTV shortly after SRS can be purported to the acute intracellular sodium overload accompanying radiation-induced cell damage, characterized by an increased cell membrane permeability as part of apoptosis and necrosis [42]. The drop of TSC below baseline 40 days after SRS can be explained by the onset of tumor shrinkage and a decreased fraction of cancer cells within the GTV as well as antiangiogenic effects of SRS [43, 44].
As demonstrated earlier by our group, mean TSC in the peritumoral tissue was elevated at baseline compared to healthy-appearing brain tissue [19]. In the current study, the peritumoral tissue within close proximity to the GTV showed the highest mean TSC, supporting the idea of peritumoral edema originating from leaky tumor vessels and its influence on TSC of the immediate surroundings in untreated brain metastases.
Shortly after SRS, we found a further, significant increase of mean TSC in the peritumoral tissue with the greatest changes in the isodose areas that had been exposed to higher radiation doses and, thus, also are within close proximity to the GTV. Isodose areas that had received doses of 6 Gy or below did not show a significant change. The peritumoral tissue recovered 40 days after SRS with TSC approaching levels of healthy brain tissue in isodose areas that had received doses of 10 Gy or below.
Regarding the histology of the primary tumors, we noted a difference between the peritumoral tissue surrounding brain metastases stemming from NSCLC (5 of 14 brain metastases) and the peritumoral tissue of brain metastases from other primaries. The peritumoral tissue of brain metastases deriving from NSCLC showed a higher mean TSC throughout all isodose areas before, shortly after, and 40 days after SRS than the peritumoral tissue of the other examined brain metastases and displayed an abrupt decrease of TSC in the isodose areas > 6 Gy at scan (I) and (II).
Very early radiation-induced injury to healthy brain tissue has been histopathologically characterized as endothelial damage with an onset hours after irradiation and (partial) restoration after 4 weeks [45–47]. DWI/PWI-MRI derived measurements have revealed SRS-induced changes in the peritumoral tissue as surrogate for vascular alterations in high dose areas receiving >10 Gy [48, 49]. Subsequently, the constantly low mean TSC in the isodose areas ≤ 10 Gy at scan (III) underlines missing or little initial tissue injury. As endothelial damage and other vascular alterations of brain tissue alone might cause an increase of TSC in the peritumoral tissue early after SRS, a combined role of the aforementioned mechanisms together with an increased tumor-derived edema seems plausible.
Regarding the different characteristic of the peritumoral tissue surrounding brain metastases from NSCLC at scan (I) and (II), previous trials evaluating the discrimination of brain metastases histology by DWI/PWI-MRI of the peritumoral tissue have reported indifferent findings [50, 51]. Here, 23Na MRI might provide helpful information, as it has been proposed for classification of glioma, but our preliminary data are not sufficient to be conclusive [41, 52].
Changes of tissue sodium concentration as an early indicator for response
We noted a further distinction in TSC behavior of the peritumoral tissue surrounding the progredient brain metastases (2 of 14 brain metastases) with homogeneously low TSC in all isodose areas before SRS and a missing surge of TSC shortly after SRS. The missing change of TSC in all isodose areas from scan (I) to scan (II) of the progredient brain metastases represents a substantial difference compared to the peritumoral tissue behavior of the responding brain metastases.
For both progredient brain metastases we recorded a comparable reaction of TSC in GTV with low concentrations at scan (I) and (II). Forty days after SRS, TSC of the peritumoral tissue was increased compared to concentrations before or shortly after SRS for the early progredient brain metastasis (soft tissue sarcoma, previously described by our group), whereas the late progredient brain metastasis (mammary carcinoma) did not exhibit a late increase of TSC, neither in the peritumoral tissue nor within the GTV [19]. The underlying mechanisms of the missing reaction of TSC within GTV or the peritumoral tissue after SRS are yet obscure and might point towards a less vascularized and thus less oxygenated tumor together with a slower tumor metabolism including a decreased mitotic rate, yielding radioresistance and a lower sodium signal.
Taken together, TSC characteristics within the GTV and TSC behaviour in the peritumoral tissue after SRS might have already indicated the unfavourable tumor response as early as 5 days post-SRS. Early response prediction at 1 month after treatment utilizing DWI/PWI-MRI has been described for a larger cohort with 70 brain metastases, but with whole brain radiotherapy or SRS as therapy option [53]. Pilot studies examining very early response prediction with DWI/PWI-MRI or chemical exchange saturation transfer (CEST)-MRI at 3 or 7 days post-SRS, respectively, have been conducted with encouraging results [54, 55]. Lastly, emerging computational prediction methods such as radiomics models or convolutional neural networks benefit from additional information that could be provided by 23Na MRI [56, 57]. This could help to identify patients who will ultimately fail SRS and allow for timelier adjustment in treatment approach.
Specifics and limitations
The here presented study must be considered a prospective feasibility study with a small sample size. The data is preliminary and warrants a pilot study with a greater sample size.
We chose a rigid volume model for the GTV and the isodose areas which did not account for volume shifts at scan (II) or (III). Early changes in size of brain metastases after SRS have been shown, but subsequent estimation of an early mass effect on the peritumoral tissue might further increase imprecision [43].
In the future, it would be of high interest to correlate the results obtained from TSC measurements in the peritumoral tissue with additional methods for the assessment of tumor progression, such as DWI or PWI measurements [12–14]. Further limitations of this study include the low spatial resolution of the 3D 23Na MR images derived from a sodium-weighted sequence, which did not allow for analysis of brain metastases with a volume of less than 64 mm3 and which implies uncertainties about the precision of isodose areas and their TSC quantification due to partial volumes effects as common problem with 23Na MRI. However, we addressed this issue by evaluating isodose areas with sufficient distance towards each other, as it is visualised in Fig 1. Distinction between intra- and extracellular TSC, in combination with ultra-high field MRI could further enhance information obtained with 23Na MRI in future trials [58].
Conclusion
Early TSC assessment within brain metastases and the peritumoral tissue after SRS with 23Na MRI is feasible. Future investigations are needed to elucidate the reasons for radiation-induced changes in TSC and their clinical value for response prediction.
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Citation: Ruder AM, Mohamed SA, Hoesl MAU, Neumaier-Probst E, Giordano FA, Schad L, et al. (2024) Radiosurgery-induced early changes in peritumoral tissue sodium concentration of brain metastases. PLoS ONE 19(11): e0313199. https://doi.org/10.1371/journal.pone.0313199
About the Authors:
Arne Mathias Ruder
Roles: Conceptualization, Data curation, Investigation, Methodology, Project administration, Writing – original draft
E-mail: [email protected]
Affiliation: Department of Radiation Oncology, University Medical Centre Mannheim, Mannheim, Germany
ORICD: https://orcid.org/0000-0002-6610-4756
Sherif A. Mohamed
Roles: Conceptualization, Data curation, Investigation, Methodology, Writing – review & editing
Affiliation: Department of Neuroradiology, University Medical Centre Mannheim, Mannheim, Germany
Michaela A. U. Hoesl
Roles: Conceptualization, Methodology
Affiliation: Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Eva Neumaier-Probst
Roles: Conceptualization, Supervision
Affiliation: Department of Neuroradiology, University Medical Centre Mannheim, Mannheim, Germany
Frank A. Giordano
Roles: Conceptualization, Supervision
Affiliation: Department of Radiation Oncology, University Medical Centre Mannheim, Mannheim, Germany
Lothar Schad
Roles: Conceptualization, Supervision
Affiliation: Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Anne Adlung
Roles: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Software, Visualization, Writing – original draft
Affiliation: Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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30. Nagy I, Lustyik G, Lukács G, Nagy V, Balázs G. Correlation of malignancy with the intracellular Na+:K+ ratio in human thyroid tumors. Cancer Res. 1983;43(11):5395–402. pmid:6616471.
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35. Cho NS, Sanvito F, Thakuria S, Wang C, Hagiwara A, Nagaraj R, et al. Multi-nuclear sodium, diffusion, and perfusion MRI in human gliomas. Journal of neuro-oncology. 2023;163(2):417–27. pmid:37294422
36. Tran TT, Mahajan A, Chiang VL, Goldberg SB, Nguyen DX, Jilaveanu LB, et al. Perilesional edema in brain metastases: potential causes and implications for treatment with immune therapy. Journal for ImmunoTherapy of Cancer. 2019;7(1):200. pmid:31362777
37. Schneider T, Kuhne JF, Bittrich P, Schroeder J, Magnus T, Mohme M, et al. Edema is not a reliable diagnostic sign to exclude small brain metastases. PloS one. 2017;12(5):e0177217. Epub 20170511. pmid:28493907; PubMed Central PMCID: PMC5426632.
38. Qian Y, Zhao T, Zheng H, Weimer J, Boada FE. High-resolution sodium imaging of human brain at 7 T. Magnetic resonance in medicine. 2012;68(1):227–33. Epub 20111205. pmid:22144258; PubMed Central PMCID: PMC3297679.
39. Thulborn K, Lui E, Guntin J, Jamil S, Sun Z, Claiborne TC, et al. Quantitative sodium MRI of the human brain at 9.4 T provides assessment of tissue sodium concentration and cell volume fraction during normal aging. NMR Biomed. 2016;29(2):137–43. Epub 20150609. pmid:26058461; PubMed Central PMCID: PMC4674376.
40. Liao Y, Lechea N, Magill AW, Worthoff WA, Gras V, Shah NJ. Correlation of quantitative conductivity mapping and total tissue sodium concentration at 3T/4T. Magnetic resonance in medicine. 2019;82(4):1518–26. Epub 20190516. pmid:31095776.
41. Regnery S, Behl NGR, Platt T, Weinfurtner N, Windisch P, Deike-Hofmann K, et al. Ultra-high-field sodium MRI as biomarker for tumor extent, grade and IDH mutation status in glioma patients. Neuroimage Clin. 2020;28:102427–. Epub 2020/09/12. pmid:33002860.
42. Adjemian S, Oltean T, Martens S, Wiernicki B, Goossens V, Vanden Berghe T, et al. Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death. Cell death & disease. 2020;11(11):1003. pmid:33230108
43. Da Silva AN, Nagayama K, Schlesinger D, Sheehan JP. Early brain tumor metastasis reduction following Gamma Knife surgery. J Neurosurg. 2009;110(3):547–52. pmid:18821832.
44. Park HJ, Griffin RJ, Hui S, Levitt SH, Song CW. Radiation-Induced Vascular Damage in Tumors: Implications of Vascular Damage in Ablative Hypofractionated Radiotherapy (SBRT and SRS). Radiation Research. 2012;177(3):311–27, 17. pmid:22229487
45. Makale MT, McDonald CR, Hattangadi-Gluth JA, Kesari S. Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours. Nat Rev Neurol. 2017;13(1):52–64. Epub 2016/12/16. pmid:27982041.
46. Ljubimova NV, Levitman MK, Plotnikova ED, Eidus L. Endothelial cell population dynamics in rat brain after local irradiation. The British journal of radiology. 1991;64(766):934–40. pmid:1954536.
47. Peña LA, Fuks Z, Kolesnick RN. Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res. 2000;60(2):321–7. pmid:10667583.
48. Winter JD, Moraes FY, Chung C, Coolens C. Detectability of radiation-induced changes in magnetic resonance biomarkers following stereotactic radiosurgery: A pilot study. PloS one. 2018;13(11):e0207933–e. pmid:30475887.
49. Jakubovic R, Sahgal A, Ruschin M, Pejović-Milić A, Milwid R, Aviv RI. Non Tumor Perfusion Changes Following Stereotactic Radiosurgery to Brain Metastases. Technol Cancer Res Treat. 2015;14(4):497–503. pmid:26269612.
50. Askaner K, Rydelius A, Engelholm S, Knutsson L, Lätt J, Abul-Kasim K, et al. Differentiation between glioblastomas and brain metastases and regarding their primary site of malignancy using dynamic susceptibility contrast MRI at 3T. J Neuroradiol. 2019;46(6):367–72. Epub 20181030. pmid:30389510.
51. Gaudino S, Di Lella GM, Russo R, Lo Russo VS, Piludu F, Quaglio FR, et al. Magnetic resonance imaging of solitary brain metastases: main findings of nonmorphological sequences. La radiologia medica. 2012;117(7):1225–41. pmid:22744350
52. Biller A, Badde S, Nagel A, Neumann JO, Wick W, Hertenstein A, et al. Improved Brain Tumor Classification by Sodium MR Imaging: Prediction of IDH Mutation Status and Tumor Progression. AJNR American journal of neuroradiology. 2016;37(1):66–73. Epub 2015/10/22. pmid:26494691.
53. Jakubovic R, Sahgal A, Soliman H, Milwid R, Zhang L, Eilaghi A, et al. Magnetic Resonance Imaging-based Tumour Perfusion Parameters are Biomarkers Predicting Response after Radiation to Brain Metastases. Clinical Oncology. 2014;26(11):704–12. pmid:25023291
54. Shah AD, Shridhar Konar A, Paudyal R, Oh JH, LoCastro E, Nuñez DA, et al. Diffusion and Perfusion MRI Predicts Response Preceding and Shortly After Radiosurgery to Brain Metastases: A Pilot Study. Journal of Neuroimaging. 2021;31(2):317–23. pmid:33370467
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Abstract
Background
Stereotactic radiosurgery (SRS) is an effective therapy for brain metastases. Response is assessed with serial 1H magnetic resonance imaging (MRI). Early markers for response are desirable to allow for individualized treatment adaption. Previous studies indicated that radiotherapy might have impact on tissue sodium concentration. Thus, 23Na MRI could provide early quantification of response to SRS.
Purpose
We investigated whether longitudinal detection of tissue sodium concentration alteration within brain metastases and their peritumoral tissue after SRS with 23Na MRI was feasible.
Study type
Prospective.
Population
Twelve patients with a total of 14 brain metastases from various primary tumors.
Assessment
23Na MRI scans were acquired from patients 2 days before, 5 days after, and 40 days after SRS. Gross tumor volume (GTV) and healthy-appearing regions were manually segmented on the MPRAGE obtained 2 days before SRS, onto which all 23Na MR images were coregistered. Radiation isodose areas within the peritumoral tissue were calculated with the radiation planning system. Tissue sodium concentration before and after SRS within GTV, peritumoral tissue, and healthy-appearing regions as well as the routine follow-up with serial MRI were evaluated.
Statistical tests
Results were compared using Student’s t-test and correlation was evaluated with Pearson’s correlation coefficient.
Results
We found a positive correlation between the tissue sodium concentration within the peritumoral tissue and radiation dosage. Two patients showed local progression and a differing tissue sodium concentration evolution within GTV and the peritumoral tissue compared to mean tissue sodium concentration of the other patients. No significant tissue sodium concentration changes were observed within healthy-appearing regions.
Conclusion
Tissue sodium concentration assessment within brain metastases and peritumoral tissue after SRS with 23Na MRI is feasible and might be able to quantify tissue response to radiation.
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Details
; Mohamed, Sherif A; Hoesl, Michaela A U; Neumaier-Probst, Eva; Giordano, Frank A; Schad, Lothar; Adlung, Anne