Cerebrovascular Reactivity Mapping Using Resting-State Functional MRI in Patients With Gliomas.

Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the CO2 inhalation-based method in health subjects and patients with neurovascular diseases. To investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas. Retrospective. Twenty-five patients (12 males, 13 females; mean age ± SD, 48 ± 13 years) with gliomas. Dynamic T2*-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T scanner. rs-CVR with various frequency ranges and resting-state fluctuation amplitude (RSFA) were assessed. The agreement between each rs-based CVR measurement and bh-CVR was determined by voxel-wise correlation and Dice coefficient in the whole brain, gray matter, and the lesion region of interest (ROI). Voxel-wise Pearson correlation, Dice coefficient, Fisher Z-transformation, repeated-measure analysis of variance and post hoc test with Bonferroni correction, and nonparametric repeated-measure Friedman test and post hoc test with Bonferroni correction were used. Significance was set at P < 0.05. Compared with bh-CVR, the highest correlations were found at the frequency bands of 0.04-0.08 Hz and 0.02-0.04 Hz for rs-CVR in both whole brain and the lesion ROI. RSFA had significantly lower correlations than did rs-CVR of 0.02-0.04 Hz and a wider frequency range (0-0.1164 Hz). Significantly higher correlations and Dice coefficient were found in normal tissues than in the lesion ROI for all three methods. The optimal frequency ranges for rs-CVR are determined by comparing with bh-CVR in patients with gliomas. The rs-CVR method outperformed the RSFA. Significantly higher correlation and Dice coefficient between rs- and bh-CVR were found in normal tissue than in the lesion. 3 TECHNICAL EFFICACY STAGE: 2.

Yeh MY ，Chen HS ，Hou P ，Kumar VA ，Johnson JM ，Noll KR ，Prabhu SS ，Ferguson SD ，Schomer DF ，Peng HH ，Liu HL ... -  《-》

Cerebrovascular Reactivity Mapping in Brain Tumors Based on a Breath-Hold Task Using Arterial Spin Labeling.

Hemodynamic measurements such as cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) can provide useful information for the diagnosis and characterization of brain tumors. Previous work showed that arterial spin labeling (ASL) in combination with vasoactive stimulation enabled simultaneous non-invasive evaluation of both parameters, however this approach had not been previously tested in tumors. The aim of this work was to investigate the application of this technique, using a pseudo-continuous ASL (PCASL) sequence combined with breath-holding at 3 T, to measure CBF and CVR in high-grade gliomas and metastatic lesions, and to explore differences across tumoral-peritumoral regions and tumor types. To that end, 27 patients with brain tumor were studied. Baseline CBF and CVR were measured in tumor, edema, and gray matter (GM) volumes-of-interest (VOIs). Peritumoral ipsilateral ring-shaped VOIs were also generated and mirrored to the contralateral hemisphere. Differences in baseline CBF and CVR were evaluated between contralateral and ipsilateral GM, contralateral and ipsilateral peritumoral rings, and among VOIs and tumor types. CBF in the tumor was higher in grade 4 gliomas than metastases. In grade 4 gliomas, edema had lower CBF than the tumor and contralateral GM. CVR values were different between grade 3 and grade 4 gliomas, and between grade 4 and metastases. CVR values in the tumor were lower compared to the contralateral GM. Differences in CVR between contralateral and ipsilateral-ring VOIs were also found in grade 4 gliomas, presumably suggesting tumor infiltration within the peritumoral tissue. A cut-off value for CVR of 27.9%-signal-change is suggested to differentiate between grade 3 and grade 4 gliomas (specificity = 83.3%, sensitivity = 70.6%). In conclusion, CBF and CVR mapping with ASL offered insights into the perilesional environment that could help to detect infiltrative disease, particularly in grade 4 gliomas. CVR emerged as a potential biomarker to differentiate between grade 3 and grade 4 gliomas.

Calvo-Imirizaldu M ，Solis-Barquero SM ，Aramendía-Vidaurreta V ，García de Eulate R ，Domínguez P ，Vidorreta M ，Echeveste JI ，Argueta A ，Cacho-Asenjo E ，Martinez-Simon A ，Bejarano B ，Fernández-Seara MA ... -  《-》

Cardiovascular risk factors are associated with cerebrovascular reactivity in young adults.

Endothelial dysfunction represents the earliest detectable stage of atherosclerosis, is associated with an increased risk of cardiovascular events, and predicts cardiovascular disease (CVD) more effectively than traditional cardiovascular risk factors. Cerebrovascular reactivity (CVR) provides an index of endothelial function in the brain. Poor CVR is associated with stroke, cerebral small vessel disease, dementia, and even coronary artery disease. Traditional CVD risk factors are associated with low CVR in patients with known CVD and in older cohorts. However, the relationship between cardiovascular risk profile and reduced CVR in young adults who do not yet have CVD is uncertain. We hypothesized that in young adults undergoing routine clinical fMRI examinations for non-vascular disease low CVR measures would be associated with increased cardiovascular risk factors. This cross-sectional study included adults with epilepsy undergoing a 3-Tesla fMRI scan of the brain for mapping of eloquent cortex with a "breath-hold task" to facilitate pre-operative planning for epilepsy-related surgery. Individuals with intracranial masses and those with baseline CVD were excluded. The task consisted of 5½, 20-s blocks of normal breathing interspersed with 20-s blocks of continuous breath holding. In breath hold fMRI scans, a voxel-wise comparison of brain T2 signal to an expected hemodynamic response curve is used to generate maps of voxel-wise t-statistics, indicating the probability that blood flow within a specific voxel had increased in response to changes in blood carbon dioxide levels. Using an axial slice 8 mm superior to the corpus callosum, a mean cerebral t-statistic was calculated for the slice as a comparative global measure of CVR in each patient. We retrospectively reviewed the charts of all individuals to characterize their clinical profile at the time of the fMRI. Based on the distribution of mean t-statistic values the sample was divided into two groups: high t-statistic ("normal reactivity") and low t-statistic value ("abnormal reactivity"). The distribution of cardiovascular risk factors was then compared across groups. Between January 2014 and December 2023, 76 individuals underwent brain fMRI employing a "breath hold task" with suitable image quality for the current analysis (mean ± SD age, 35.46 ± 12.09 yrs.; 31.6 % female). Mean ± SD global CVR T-statistic was 3.97 ± 1.62. Low CVR was defined as a mean T-statistic ≤4.2 (n = 44, 57.9 %). Individuals with abnormal CVR were older (age: 45.1 ± 10.3 vs. 27.0 ± 3.4 yrs., p < 0.001), had a higher frequency of hypertension (31.8 % vs. 14.3 %, p = 0.0069) and hyperlipidemia (18.2 % vs. 3.1 %, p = 0.0449), and had higher systolic (123.5 ± 13.2 vs. 116.9 ± 12.2 mmHg, p = 0.0282) and diastolic blood pressures (77.9 ± 11.8 vs. 72.2 ± 8.9, p = 0.0141). Age, systolic blood pressure and hyperlipidemia were significantly associated with abnormal CVR in univariable and multivariable analyses (age, increase by 10 years OR: 2.00, 95 % CI 1.40-2.78, p = 0.0078; hyperlipidemia OR: 8.54, 95 % CI 1.07-184.9, p = 0.0049, and systolic blood pressure (OR for an increase in 10 mmHg: 1.57, 95 % CI 1.10-2.10, p = 0.0084). Traditional cardiovascular risk factors, specifically age, systolic blood pressure and hyperlipidemia, are significantly associated with abnormal CVR in young adults without baseline CVD or cerebrovascular disease undergoing fMRI for reasons related to a diagnosis of epilepsy.

Sara JDS ，Pillai JJ ，Lerman LO ，Lerman A ，Welker K ... -  《-》

Super-resolution reconstruction of time-resolved four-dimensional computed tomography (TR-4DCT) with multiple breathing cycles based on TR-4DMRI.

Respiratory motion irregularities in lung cancer patients are common and can be severe during multi-fractional (∼20 mins/fraction) radiotherapy. However, the current clinical standard of motion management is to use a single-breath respiratory-correlated four-dimension computed tomography (RC-4DCT or 4DCT) to estimate tumor motion to delineate the internal tumor volume (ITV), covering the trajectory of tumor motion, as a treatment target. To develop a novel multi-breath time-resolved (TR) 4DCT using the super-resolution reconstruction framework with TR 4D magnetic resonance imaging (TR-4DMRI) as guidance for patient-specific breathing irregularity assessment, overcoming the shortcomings of RC-4DCT, including binning artifacts and single-breath limitations. Six lung cancer patients participated in the IRB-approved protocol study to receive multiple T1w MRI scans, besides an RC-4DCT scan on the simulation day, including 80 low-resolution (lowR: 5 × 5 × 5 mm3) free-breathing (FB) 3D cine MRFB images in 40 s (2 Hz) and a high-resolution (highR: 2 × 2 × 2 mm3) 3D breath-hold (BH) MRBH image for each patient. A CT (1 × 1 × 3 mm3) image was selected from 10-bin RC-4DCT with minimal binning artifacts and a close diaphragm match (<1 cm) to the MRBH image. A mutual-information-based Freeform deformable image registration (DIR) was used to register the CT and MRBH via the opposite directions (namely F1: C T Source → MR Target BH ${\mathrm{C}}{{{\mathrm{T}}}_{{\mathrm{Source}}}} \to {\mathrm{MR}}_{{\mathrm{Target}}}^{{\mathrm{BH}}}$ and F2: C T Target ← MR Source BH ${\mathrm{C}}{{{\mathrm{T}}}_{{\mathrm{Target}}}} \leftarrow {\mathrm{MR}}_{{\mathrm{Source}}}^{{\mathrm{BH}}}$ ) to establish CT-MR voxel correspondences. An intensity-based enhanced Demons DIR was then applied for MR Source BH → MR Target FB ${\mathrm{MR}}_{{\mathrm{Source}}}^{{\mathrm{BH}}} \to {\mathrm{MR}}_{{\mathrm{Target}}}^{{\mathrm{FB}}}$ , in which the original MRBH was used in D1: C T Source → ( MR Source BH → MR Target FB ) Target ${\mathrm{C}}{{{\mathrm{T}}}_{{\mathrm{Source}}}} \to {{({\mathrm{MR}}_{{\mathrm{Source}}}^{{\mathrm{BH}}} \to {\mathrm{MR}}_{{\mathrm{Target}}}^{{\mathrm{FB}}})}_{{\mathrm{Target}}}}$ , while the deformed MRBH was used in D2: ( C T Target ← MR Source BH ) Source → MR Target FB ${{( \text{C}{{\text{T}}_{\text{Target}}}\leftarrow \text{MR}_{\text{Source}}^{\text{BH}} )}_{\text{Source}}}\to \text{MR}_{\text{Target}}^{\text{FB}}$ . The deformation vector fields (DVFs) obtained from each DIR were composed to apply to the deformed CT (D1) and original CT (D2) to reconstruct TR-4DCT images. A digital 4D-XCAT phantom at the end of inhalation (EOI) and end of exhalation (EOE) with 2.5 cm diaphragmatic motion and three spherical targets (ϕ = 2, 3, 4 cm) were first tested to reconstruct TR-4DCT. For each of the six patients, TR-4DCT images at the EOI, middle (MID), and EOE were reconstructed with both D1 and D2 approaches. TR-4DCT image quality was evaluated with mean distance-to-agreement (MDA) at the diaphragm compared with MRFB, tumor volume ratio (TVR) referenced to MRBH, and tumor shape difference (DICE index) compared with the selected input CT. Additionally, differences in the tumor center of mass (|∆COMD1-D2|), together with TVR and DICE comparison, was assessed in the D1 and D2 reconstructed TR-4DCT images. In the phantom, TR-4DCT quality is assessed by MDA = 2.0 ± 0.8 mm at the diaphragm, TVR = 0.8 ± 0.0 for all tumors, and DICE = 0.83 ± 0.01, 0.85 ± 0.02, 0.88 ± 0.01 for ϕ = 2, 3, 4 cm tumors, respectively. In six patients, the MDA in diaphragm match is -1.6 ± 3.1 mm (D1) and 1.0 ± 3.9 mm (D2) between the reconstructed TR-4DCT and lowR MRFB among 18 images (3 phases/patient). The tumor similarity is TVR = 1.2 ± 0.2 and DICE = 0.70 ± 0.07 for D1 and TVR = 1.4 ± 0.3 (D2) and DICE = 0.73 ± 0.07 for D2. The tumor position difference is |∆COMD1-D2| = 1.2 ± 0.8 mm between D1 and D2 reconstructions. The feasibility of super-resolution reconstruction of multi-breathing-cycle TR-4DCT is demonstrated and image quality at the diaphragm and tumor is assessed in both the 4D-XCAT phantom and six lung cancer patients. The similarity of D1 and D2 reconstruction suggests consistent and reliable DIR results. Clinically, TR-4DCT has the potential for breathing irregularity assessment and dosimetry evaluation in radiotherapy.

Liu Y ，Nie X ，Ahmad A ，Rimner A ，Li G ... -  《-》

Comparison of Two Modern Survival Prediction Tools, SORG-MLA and METSSS, in Patients With Symptomatic Long-bone Metastases Who Underwent Local Treatment With Surgery Followed by Radiotherapy and With Radiotherapy Alone.

Survival estimation for patients with symptomatic skeletal metastases ideally should be made before a type of local treatment has already been determined. Currently available survival prediction tools, however, were generated using data from patients treated either operatively or with local radiation alone, raising concerns about whether they would generalize well to all patients presenting for assessment. The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA), trained with institution-based data of surgically treated patients, and the Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy model (METSSS), trained with registry-based data of patients treated with radiotherapy alone, are two of the most recently developed survival prediction models, but they have not been tested on patients whose local treatment strategy is not yet decided. (1) Which of these two survival prediction models performed better in a mixed cohort made up both of patients who received local treatment with surgery followed by radiotherapy and who had radiation alone for symptomatic bone metastases? (2) Which model performed better among patients whose local treatment consisted of only palliative radiotherapy? (3) Are laboratory values used by SORG-MLA, which are not included in METSSS, independently associated with survival after controlling for predictions made by METSSS? Between 2010 and 2018, we provided local treatment for 2113 adult patients with skeletal metastases in the extremities at an urban tertiary referral academic medical center using one of two strategies: (1) surgery followed by postoperative radiotherapy or (2) palliative radiotherapy alone. Every patient's survivorship status was ascertained either by their medical records or the national death registry from the Taiwanese National Health Insurance Administration. After applying a priori designated exclusion criteria, 91% (1920) were analyzed here. Among them, 48% (920) of the patients were female, and the median (IQR) age was 62 years (53 to 70 years). Lung was the most common primary tumor site (41% [782]), and 59% (1128) of patients had other skeletal metastases in addition to the treated lesion(s). In general, the indications for surgery were the presence of a complete pathologic fracture or an impending pathologic fracture, defined as having a Mirels score of ≥ 9, in patients with an American Society of Anesthesiologists (ASA) classification of less than or equal to IV and who were considered fit for surgery. The indications for radiotherapy were relief of pain, local tumor control, prevention of skeletal-related events, and any combination of the above. In all, 84% (1610) of the patients received palliative radiotherapy alone as local treatment for the target lesion(s), and 16% (310) underwent surgery followed by postoperative radiotherapy. Neither METSSS nor SORG-MLA was used at the point of care to aid clinical decision-making during the treatment period. Survival was retrospectively estimated by these two models to test their potential for providing survival probabilities. We first compared SORG to METSSS in the entire population. Then, we repeated the comparison in patients who received local treatment with palliative radiation alone. We assessed model performance by area under the receiver operating characteristic curve (AUROC), calibration analysis, Brier score, and decision curve analysis (DCA). The AUROC measures discrimination, which is the ability to distinguish patients with the event of interest (such as death at a particular time point) from those without. AUROC typically ranges from 0.5 to 1.0, with 0.5 indicating random guessing and 1.0 a perfect prediction, and in general, an AUROC of ≥ 0.7 indicates adequate discrimination for clinical use. Calibration refers to the agreement between the predicted outcomes (in this case, survival probabilities) and the actual outcomes, with a perfect calibration curve having an intercept of 0 and a slope of 1. A positive intercept indicates that the actual survival is generally underestimated by the prediction model, and a negative intercept suggests the opposite (overestimation). When comparing models, an intercept closer to 0 typically indicates better calibration. Calibration can also be summarized as log(O:E), the logarithm scale of the ratio of observed (O) to expected (E) survivors. A log(O:E) > 0 signals an underestimation (the observed survival is greater than the predicted survival); and a log(O:E) < 0 indicates the opposite (the observed survival is lower than the predicted survival). A model with a log(O:E) closer to 0 is generally considered better calibrated. The Brier score is the mean squared difference between the model predictions and the observed outcomes, and it ranges from 0 (best prediction) to 1 (worst prediction). The Brier score captures both discrimination and calibration, and it is considered a measure of overall model performance. In Brier score analysis, the "null model" assigns a predicted probability equal to the prevalence of the outcome and represents a model that adds no new information. A prediction model should achieve a Brier score at least lower than the null-model Brier score to be considered as useful. The DCA was developed as a method to determine whether using a model to inform treatment decisions would do more good than harm. It plots the net benefit of making decisions based on the model's predictions across all possible risk thresholds (or cost-to-benefit ratios) in relation to the two default strategies of treating all or no patients. The care provider can decide on an acceptable risk threshold for the proposed treatment in an individual and assess the corresponding net benefit to determine whether consulting with the model is superior to adopting the default strategies. Finally, we examined whether laboratory data, which were not included in the METSSS model, would have been independently associated with survival after controlling for the METSSS model's predictions by using the multivariable logistic and Cox proportional hazards regression analyses. Between the two models, only SORG-MLA achieved adequate discrimination (an AUROC of > 0.7) in the entire cohort (of patients treated operatively or with radiation alone) and in the subgroup of patients treated with palliative radiotherapy alone. SORG-MLA outperformed METSSS by a wide margin on discrimination, calibration, and Brier score analyses in not only the entire cohort but also the subgroup of patients whose local treatment consisted of radiotherapy alone. In both the entire cohort and the subgroup, DCA demonstrated that SORG-MLA provided more net benefit compared with the two default strategies (of treating all or no patients) and compared with METSSS when risk thresholds ranged from 0.2 to 0.9 at both 90 days and 1 year, indicating that using SORG-MLA as a decision-making aid was beneficial when a patient's individualized risk threshold for opting for treatment was 0.2 to 0.9. Higher albumin, lower alkaline phosphatase, lower calcium, higher hemoglobin, lower international normalized ratio, higher lymphocytes, lower neutrophils, lower neutrophil-to-lymphocyte ratio, lower platelet-to-lymphocyte ratio, higher sodium, and lower white blood cells were independently associated with better 1-year and overall survival after adjusting for the predictions made by METSSS. Based on these discoveries, clinicians might choose to consult SORG-MLA instead of METSSS for survival estimation in patients with long-bone metastases presenting for evaluation of local treatment. Basing a treatment decision on the predictions of SORG-MLA could be beneficial when a patient's individualized risk threshold for opting to undergo a particular treatment strategy ranged from 0.2 to 0.9. Future studies might investigate relevant laboratory items when constructing or refining a survival estimation model because these data demonstrated prognostic value independent of the predictions of the METSSS model, and future studies might also seek to keep these models up to date using data from diverse, contemporary patients undergoing both modern operative and nonoperative treatments. Level III, diagnostic study.

Lee CC ，Chen CW ，Yen HK ，Lin YP ，Lai CY ，Wang JL ，Groot OQ ，Janssen SJ ，Schwab JH ，Hsu FM ，Lin WH ... -  《-》