T2 Lesions Research Articles

The correlation of conventional and advanced MRI findings with cognitive function in multiple sclerosis: A systematic review and meta-analysis

There are limited data on the possible association between conventional and advanced magnetic resonance imaging (MRI) findings and cognitive function in patients with multiple sclerosis (MS). Therefore, this systematic review and meta-analysis aimed to explore the correlation between MRI-derived metrics and cognitive tests in patients with MS. An electronic literature search of the PubMed, Web of Sciences, Embase, and Scopus databases was performed to identify related studies. The correlation coefficients of the MRI indices and cognitive tests were pooled. Thirteen studies were selected for inclusion of 824 patients diagnosed with MS. Most evaluated patients (60.44%) had relapsing-remitting MS (RRMS). The Paced Auditory Serial Addition Test (PASAT-3), Brief Visuospatial Memory Test (BVMT), and Symbol Digit Modalities Test (SDMT) were inversely correlated with the mean diffusivity (MD) of the brain with pooled correlation coefficient of -0.225, -0.361, and -0.438, respectively (P<0.0001). The SDMT test positively correlated with fractional anisotropy (FA) with a correlation coefficient of 0.351 (P<0.0001) and inversely correlated with T2 lesion volume with a correlation coefficient of -0.367 (P<0.0001). In the case of other tests, there was low number of studies with significant correlations being reported. We found significant correlations between some neuropsychological tests and MRI findings in patients with MS. Brain atrophy might disrupt the process of correct registration between anatomical and MRI diffusion scans. However, we did not have enough studies with exactly matched anatomical areas to evaluate correlations and we recommend that histological validation of diffusion tensor imaging (DTI) findings for brain atrophy is needed as a basis for picture processing procedures and correlation with cognition status.

Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS)

BackgroundExtended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals.MethodsThe...

Brain volume increase after discontinuing natalizumab therapy: Evidence for reversible pseudoatrophy

BackgroundThe phenomenon of pseudoatropy after initiation of anti-inflammatory therapy is believed to be reversible, but a rebound in brain volume following cessation of highly-effective therapy has not been reported. ObjectivesTo evaluate brain volume change in a treatment interruption study (RESTORE) in which relapsing-remitting multiple sclerosis (RRMS) patients were randomized to switch from natalizumab to placebo, from natalizumab to once-monthly intravenous methylprednisolone (IVMP), or to remain on natalizumab. MethodsT2 lesion volume (T2LV), baseline normalized brain volumes, and follow-up percent brain volume changes (PBVC) were calculated. Approximate T2 relaxation-time (pT2) was calculated within the brain mask and the T2 lesions to estimate changes in water content. Linear mixed effects models were used to detect differences in T2LV, pT2 in whole brain, pT2 in T2-weighted lesions, and PBVC among the placebo, natalizumab, and IVMP groups. We also estimated contributions of T2LV and pT2 (in whole brain and T2 lesions) to PBVC. ResultsT2LV increased in the placebo group (by 0.66 ml/year, p<0.0001) and IVMP (+1.98 ml/year, p = 0.05) groups relative to the natalizumab group. The rates of PBVC were significantly different: −0.239%/year with continued natalizumab and +0.126 %/year after switch to placebo (p = 0.03), while the IVMP group showed brain volume loss (−0.74 %/ year, p = 0.08). pT2 was not statistically different between the groups (p ≥ 0.29) and did not have significant effects on PBVC (p ≥ 0.25). ConclusionThe increase in the brain volume in patients witching from natalizumab to placebo is consistent with reversal of so-called pseudoatrophy after starting natalizumab.

RADT-26. IMPROVING RADIATION TARGET VOLUME DEFINITION FOR GLIOBLASTOMA USING PREDICTIONS OF TUMOR RECURRENCE FROM MACHINE LEARNING AND PRE-RADIOTHERAPY ADVANCED MRI

Abstract INTRODUCTION Standard-of-care (SOC) radiation therapy (RT) planning only utilizes a fairly 1.5-2cm uniform expansion of T2-weighted-FLAIR MRI lesion to generate a clinical target volume (2cm-CTV), without considering the spatial heterogeneity and infiltrative nature of glioblastomas. This study aimed to use multi-parametric MRI with 2 artificial intelligence (AI)-based approaches to predict regions of subsequent tumor progression and compare the resulting predictions to the 2cm-CTV, with the hypothesis that applying deep learning will lead to improved detection of subclinical disease that is under-treated, and more accurately delineate areas at higher risk for progression, than the uniform 2cm-CTV. METHODS We used normalized maps of anatomical, diffusion, and metabolic MRI post-surgical resection and before RT and chemotherapy from 72 patients newly-diagnosed with glioblastoma to train Random-Forest and deep-learning UNet models to identify voxels that later exhibit progression by either the contrast-enhancing-lesion (CEL) or T2-lesion (T2L). All models were trained/validated on 54 and tested on 18 patients after careful inter-exam alignment and normalization. Model performance was compared to the 2cm-CTV using a Progression-Coverage-Coefficient (PCC), a weighted Dice coefficient that accounts for tumor-size. RESULTS Random-Forest models were able to predict subsequent contrast-enhancing (CE) and T2 non-enhancing (NE) progression with an average respective test AUC of 0.88 and 0.82, with 15.6%/9.6% higher performance on patients who progressed early. The 2cm-CTV treatment plan achieved the highest sensitivity (0.833 vs 0.795) but also the lowest specificity (0.879 vs 0.935), over-treating normal-appearing-brain. Our deep learning model outperformed the 2cm-CTV in covering the progressed lesion, with the highest specificity (0.935 vs 0.879), PCC (0.741 vs 0.734), and had comparable sensitivity (0.795) to the 2cm-CTV, while sparing more normal brain compared to the 2cm-CTV. CONCLUSION This study demonstrates the potential benefit of using multi-parametric MRI with deep learning to assist in RT treatment planning to reduce excessive treatment of normal brain parenchyma.

Macular Neovascularization Type Influence on Anti-VEGF Intravitreal Therapy Outcomes in Age-Related Macular Degeneration

PurposeTo evaluate the influence of macular neovascularization (MNV) lesion type on 12 months clinical outcomes in treatment-naïve eyes with age-related macular degeneration (nAMD) eyes treated with anti-vascular endothelial growth factor (VEGF) drugs nationwide. DesignMulticenter national nAMD database observational study. SubjectsOne thousand six-hundred six treatment-naïve nAMD eyes (1330 patients) undergoing Anti-VEGF therapy for 12 months nationwide. MethodsDemographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters, number of injections and visits data was collected using a validated web-based tool. Neovascular lesion phenotype was classified as type 1 (T1, n=711), type 2 (T2, n=505), type 3 (T3, n=315) and aneurysmal type 1 (A-T1, n=75), according to the new proposed consensus classification. Main outcome measuresMean VA change at 12 months, final VA at 12 months, number of injections, time to lesion inactivation. ResultsA total of 1606 treatment-naïve nAMD eyes (1330 patients) received a median of 7 injections over 12 months. Mean (±standard deviation) baseline VA was significantly lower for T2 (49.4±23.5 letters) compared to T1 (57.8±20.8) and T3 (58.2 ±19.4)(both p<0.05) lesions. Mean VA change at 12 months was significantly greater for A-T1 (+9.5 letters) compared to T3 (+3.1 letters, p<0.05). T3 lesions had fewer active visits (24.9%) than the other lesion types (T1 30.5%, T2 32.6%, A-T1 27.5%, all p<0.05). Aflibercept was the most used drug in A-T1 lesions (70.1%) and ranibizumab in T1 (40.7%), T2 (57.7%) and T3 (47.6%) lesions. ConclusionsThis study highlights the relevance of MNV type on clinical outcomes in nAMD and reports significant differences in baseline VA, VA change and lesion activity at 12 months. This report provides data about lesion-specific clinical features, which may guide the management of nAMD cases and potentially support a personalized clinical decision making in these patients.

34 Verbal Memory as a Language Function: Phonological Processing Contributes to Word List Recall in Persons with Multiple Sclerosis

Objective:Verbal memory deficits are present in multiple sclerosis (MS), but neither inflammatory T2 lesion volume nor cerebral atrophy (generalized or localized hippocampal atrophy) fully explain disease-related verbal memory changes. Importantly, the hippocampus does not function in a vacuum; memory encoding and retrieval requires interactions between the hippocampus and cortical areas where information is processed and represented. Indeed, we have previously shown that lexical access speed (a language function assessed by rapid automatized naming) independently predicted delayed recall of verbal information (word list) for persons with MS, even when controlling for total learning. Informed by this work and recent ultra high field (7.0 Tesla) MRI research reporting high cortical lesion count in regions associated with phonological processing (e.g., plenum temporale, superior temporal gyrus), we assessed whether phonological processing independently explains verbal memory deficits in persons with MS.Participants and Methods:Analyses were performed on a clinical sample of persons with MS aged 18 to 59 years (n=60: 49 relapsing, 11 progressive). Word-list memory was assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R), which yielded scores for Total Learning (TL) and Delayed Recall (DR). Phonological processing was assessed with WIAT-4 Phonemic Proficiency. WIAT-4 Sentence Repetition was utilized as a non-phonological language control task, and WIAT-4 Word Reading was administered to control for premorbid verbal ability. CANTAB Paired Associate Learning served as a nonverbal memory comparison. Performance on tasks was standardized using published age-adjusted norms. Primary analyses used partial correlations to assess relationships between Phonemic Proficiency and (a) HVLT-R TL and DR controlling for WIAT-4 Word Reading, and (b) HVLT-R DR controlling for WIAT-4 Word Reading and HVLT-R TL. To assess specificity to phonological processing, the same partial correlations assessed relationships between Sentence Repetition and HVLT-R variables, and between Phonemic Proficiency and nonverbal memory (CANTAB PAL).Results:When controlling for premorbid verbal ability, Phonemic Proficiency performance accounted for 7.8% of the variance in HVLT-R TL (rpartial=0.28, p=0.031) and 16% of the variance in HVLT-R DR (rpartial=0.40, p=0.002). Moreover, when additionally controlling for HVLT-R TL, Phonemic Proficiency still accounted for 10% of the variance in HVLT-R DR (r partial— 0.32, p=0.016). Showing specificity to phonological processing ability, performance on Sentence Repetition was not significantly related to HVLT-R DR when controlling for premorbid verbal ability (WIAT-4 Word Reading) and HVLT-R TL (rpartial=0.09, p=0.510). Showing specificity to verbal memory, neither Phonemic Proficiency nor Sentence Repetition performance were reliably related to CANTAB PAL for any variance in performance in nonverbal memory (Ps&gt;0.9).Conclusions:Results suggest that language ability, specifically phonological processing, contributes to delayed recall of word lists independent of premorbid verbal ability and initial total learning scores in persons with MS. These findings demonstrate contributions of language ability to verbal memory and highlight the need for further research into language ability changes in persons with MS. This may have implications for verbal memory rehabilitation in MS.

Stem Cell Transplantation for Multiple Sclerosis: A 2023 Review of Published Studies.

This comprehensive literature review underscores the potential of stem cell transplantation (SCT) as a therapeutic intervention for multiple sclerosis (MS). By amalgamating evidence from various sources, including randomized controlled trials (RCTs), observational, retrospective, and comparative studies, this review offers a holistic understanding of SCT's effectiveness, safety, and feasibility in diverse contexts of MS management. SCT has shown promise in mitigating disease activity and progression, particularly in relapsing-remitting MS (RRMS). RCTs like the high dose immunoablation and autologous hematopoietic stem cell transplantation in MS (ASTIMS) versus mitoxantrone therapy in severe multiple sclerosis and multiple sclerosis international stem cell transplant (MIST) trials reveal SCT's capacity to reduce new lesion occurrences and inflammatory activity. However, variability exists in disability score improvements among these studies. Observational and retrospective investigations further affirm SCT's potential, highlighting decreased relapse rates, enhanced expanded disability status scale (EDSS) scores, and a noteworthy proportion of patients achieving no evidence of disease activity (NEDA). The initial literature search using all of the search items produced a total of 3,636 articles. After title, abstract, and article type screening and article retrieving, 147 articles were assessed for eligibility using the inclusion criteria. At the end of the literature search, 37 articles met the eligibility criteria. They were included in our review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Patients treated with hematopoietic stem cell transplantation (HSCT) present lower progression and relapse rates, suppression of inflammatory activity, and a greater reduction in T2 lesions on MRI than those treated with disease-modifying therapies (DMTs). In summary, while SCT presents promise as a therapeutic option for MS, its deployment should be tailored to individual patient characteristics, disease stages, and responses.

Real-life safety and effectiveness outcomes of teriflunomide in patients with relapsing–remitting multiple sclerosis: The TERICAM study

Introduction and objectiveTeriflunomide is an oral immunomodulatory agent approved for the treatment of relapsing–remitting multiple sclerosis (RRMS). We examined teriflunomide outcomes in patients with RRMS under clinical practice conditions in Spain. Material and methodsNon-interventional, retrospective study at 15 sites in the Autonomous Region of Madrid and nearby regions. Effectiveness (relapses, EDSS, gadolinium-enhancing T1 lesions and new/enlarged T2-weighted lesions), safety (adverse events), and reasons for discontinuation during the 24 months after teriflunomide initiation were reported. ResultsA total of 776 patients were included (mean [SD] age was 43.3 (9.8) years; 69.3% were female). Two-thirds (67.7%) of patients had received a prior treatment, with beta-interferons or glatiramer acetate (BRACE) as the most frequent (93.5%) treatment. After 24 months, teriflunomide significantly reduced the annualized relapse rate (ARR) by 72% (mean [95% confidence interval] 0.12 [0.10, 0.14] vs 0.43 [0.40, 0.47] at baseline; P<.0001) and 81.8% of patients were relapse-free. The number of patients with gadolinium-enhancing T1 lesions and new/enlarged lesions on T2 was also reduced after 24 months of teriflunomide treatment (P<.001). Mean EDSS (SD) score was 1.9 (1.5) at teriflunomide initiation and 2.0 (1.6) at month 24. Half of patients (n=388) reported at least 1 adverse event (AE; gastrointestinal disorders: 26.2%; hair thinning: 25%; and elevation of ALT values: 12.9%). Most patients (91.5%) did not show fatigue increase during teriflunomide treatment. Among patients who discontinued treatment (n=262; 34.2%), the most common reasons were lack of effectiveness (58.0%), AEs (31.9%; n=82), and pregnancy desire (6.6%; n=17). ConclusionsMost RRMS patients treated with teriflunomide in clinical practice had received prior treatments. Teriflunomide resulted in decreased clinical and radiological activity and disability stabilization. AE frequency and type were in line with prior reports. Most patients did not experience fatigue increases after teriflunomide initiation.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study

BackgroundThe assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI...

Real-World Experience of Intensity Modulated Radiation Therapy and Concurrent Chemotherapy for Anal Cancer with Long-Term Follow up and Clinical Outcomes

The standard treatment for epidermoid anal cancer (AC) is concurrent chemoradiation (CRT). Here we present real world evidence of the safety and outcomes of AC patients managed by IMRT and concurrent chemotherapy at a single academic cancer center. We retrospectively reviewed the outcomes of 180 AC patients treated with definitive CRT between 2011 and 2018. Patients were managed according to a prospectively designed protocol of IMRT with radiation dose escalated according to tumor stage: 50.4, 55.8 and 63 Gy for T1, T2 and T3/T4 disease respectively, and 36 Gy for elective nodal RT. Involved nodes were given the same dose based on T category. Concurrent chemotherapy consisted of two cycles of mitomycin C (MMC, 12 mg/m2) and 5-fluorouracil (5FU, 1000 mg/m2/day x 4 days) given on week 1 and 5. There was no planned treatment break. Univariate and multivariate analysis for outcomes were performed using Cox proportional hazard method and likelihood ratio statistics. Overall survival (OS) disease free (DFS), colostomy-free survival (CFS) and local failure rates (LFR) were described by Kaplan-Meier methods. There were 128 female and 52 male patients with a median age of 64 (IQR 55-74). The median size of the primary was 4.0 cm (0.6-11.0 cm). There were 18 T1, 91 T2, 38 T3 and 33 T4 lesions; 50.6% (91/180) of the patients had N0 disease. Thirteen (7.2%) did not receive concurrent chemotherapy, and 16 (8.9%) failed to complete treatment as planned. Forty-three (23.9%) patients had a treatment gap >5 (6-33) days. Eighteen of 147 (12%) with T1-3 disease failed locally, LF was observed in 13/33 (39%) T4 lesions (P = 0.0002). The 5-year OS, DFS, CFS and LFR were 85.1%, 75.6%, 87.6% and 15.5% respectively. On multivariate analysis, increasing age and N+ disease were significant for worse OS, and increasing size of the primary tumor was the only significant factor for worse DFS, CFS and LFR. Grade ≥3 acute toxicities were observed in 42.8% of patients, with grade ≥3 neutropenia and febrile neutropenia observed in 18.9% and 13.9% of patients respectively. Six patients (3.3%) died of acute toxicities. Thirteen (7%) patients experienced grade ≥3 late toxicities. Size of the primary appears to be the most important determinant of outcome following standard CRT using IMRT for AC. Despite IMRT, almost 1 in 4 patients required a treatment break, and over 40% experienced grade ≥3 acute toxicities including neutropenia and febrile neutropenia. Future studies with RT dose escalation or de-escalation, stratifying patients based on tumor size, HPV status and molecular markers are necessary to improve outcomes and decrease treatment related toxicity.

A Survey Study of Practice Patterns in Management of Very Early Small Cell Lung Cancer in Canada

Concurrent chemoradiotherapy (CRT) is the gold standard in management of limited-stage small cell lung cancer (LS-SCLC). Local therapy with surgery or stereotactic radiotherapy (SBRT), followed by adjuvant chemotherapy may be appropriate in patients with very early (T1-T2, N0) disease. This study aimed to determine practice patterns for very early LS-SCLC among lung cancer specialists in Canada. A survey was developed and distributed to Canadian medical and radiation oncologists specializing in lung cancer. The survey consisted of three sections: 1) physician demographics, 2) general practice approach, and 3) preferred approach for three clinical scenarios (1: a peripheral T1 lesion; 2: a central T1 lesion; 3: a peripheral T2 lesion). Responses were analyzed to detect differences in management across cases and among various physician groups. A total of 77 physicians participated. In case 1, when the patient was eligible for surgery, most respondents (73%) chose surgery with adjuvant chemotherapy as their preferred management, with only 19% choosing CRT. CRT was selected by a higher proportion in case 2 (48%) and case 3 (61%) (p<0.05). If medically operable, most chose CRT over SBRT and adjuvant chemotherapy in all cases. CRT was significantly more popular in case 2 (84%) and case 3 (86%) than in case 1 (55%) (p<0.05). Subgroup analysis showed physicians from Western Canadian were more likely to choose CRT, those from Ontario were more likely to offer SBRT, and those who have spent longer in practice were more likely to choose CRT over local therapy. There is no clear consensus regarding optimal management of patients with very early LS-SCLC among specialists in Canada, with significant variations in practice patterns. CRT remains the most popular strategy in most cases, with surgery and adjuvant chemotherapy preferred for small peripheral lesions. Increasing size of tumor as well as more central location are factors that drive physicians towards choosing CRT. Variation in practice is correlated to region of the country and to physician experience.

Long-Term Toxicity in Patients Receiving Radiotherapy for Ultracentral Stage I Non-Small Cell Lung Cancer – A Secondary Analysis of the LUSTRE Randomized Trial

Hypofractionated and stereotactic body radiotherapy (SBRT) are increasingly used in the treatment of centrally located, early-stage non-small cell lung cancer (NSCLC), though there are concerns of increased morbidity and mortality in patients with ultracentral tumors (UC). We report on the long-term toxicity of patients with UC lung cancer treated on a prospective randomized clinical trial of SBRT versus conventionally hypofractionated radiotherapy (CRT) for stage I NSCLC (NCT01968941). Patients with UC tumors, defined as those where the planning target volume directly overlaps with the proximal bronchial tree (PBT), were identified from the larger cohort of patients treated on the trial. These patients received either SBRT with 60 Gy in 8 fractions or CRT with 60 Gy in 15 fractions. The primary endpoint of this secondary analysis was development of any grade 3 or higher toxicity defined using CTCAE version 3.0. Secondary endpoints included local control, as well as dosimetric analysis of the PBT, using EQD2 with α/β ratio of 3 to assess the relationship between dose to the PBT and toxicity. Twenty-nine patients were identified with UC tumors; 21 received SBRT and 8 received CRT. Median age was 72 years (range 55-88 years) and 59% were female. Median FEV1 was 1.46L (range 0.64-2.37L). Patients had either T1 (59%) or T2 (41%) lesions, with median tumor size 2.5cm (range 1.1-4.9cm). Most patients had histologically confirmed disease (squamous cell, n = 10; adenocarcinoma, n = 8; radiographically suspicious, n = 11). The median follow-up was 2.9 years (range 0.7-5.2 years). The 3-year local control rate of all patients was 88.3% (95% confidence interval: 75.7-100%). There were 3 patients with late (>3 months) grade 3 toxicity (bronchial stricture, chest pain, and atelectasis) and 1 patient with late grade 5 toxicity (bleeding/hemorrhage), all treated in the SBRT arm. Median EQD2 dose to PBT in patients with grade ≥3 late toxicity compared to the rest of the cohort was: Dmax, 132 vs 129 Gy; D0.1cc, 129 vs 119 Gy; D1cc, 124 vs 80 Gy; and D5cc, 83 vs 41 Gy. Median EQD2 volumetric doses in grade ≥3 patients (compared to the rest) to PBT were: V65 Gy, 9.7 vs 2.2cc; V80 Gy, 7.9 vs 1.1cc; V90 Gy, 6.2 vs 0.4cc; and V100 Gy, 4.8 vs 0.3cc. The single patient with grade 5 toxicity had the highest D5cc (116 Gy) and V100 Gy (7cc) among all patients. Stereotactic radiation with 60 Gy in 8 fractions for UC lung cancer provides good local control but carries an approximately 15-20% rate of late grade ≥3 toxicity. There appears to be a dosimetric association between toxicity and dose to the PBT. It may be more important to minimize volumetric PBT dose rather than maximum point dose to reduce risk of severe late toxicity.

Prognostic Value of Weekly Delta-Radiomics during MR-Linac Radiotherapy of Glioblastoma

MRI after chemoradiotherapy (chemoRT) shows areas of presumed tumor growth in ≤ 50% of glioblastoma (GBM) patients, which can be true progression (TP) - tumor growth with poor treatment response, or pseudoprogression (PP) - edema and tumor necrosis with favorable treatment response. Patients with TP have median overall survival (OS) of only 7 months, while patients with PP have median OS of 36 months. However, on imaging, TP and PP are usually not discernible during treatment, making it difficult to adapt radiation for poor responders. The purpose of this study was to investigate the prognostic value of delta radiomic features from MR-Linac for GBM. Using an IRB-approved prospective cohort of GBM patients undergoing 30 fractions of chemoRT to 60 Gy on a 0.35T MR-Linac, 2 regions of interest (ROI) were contoured on daily T2-weighted treatment set-up scans: 1) tumor/edema (lesion) and 2) post-surgical resection cavity (RC). The lesion ROI were used to calculate texture features: second order radiomics features based on the gray-level co-occurrence matrix (GLCM), gray-level size zone matrix (GLSZM), gray-level run length matrix (GLRLM), and neighborhood gray-tone difference matrix (NGTDM). Each of these describe the probability of spatial relationships of gray levels occurring within the ROI. Features from fraction 1 (pre-radiation) were subtracted from fractions 5, 10, 15, 25, and 30 to create delta features at 5 timepoints (D5-D30). Patient response was retrospectively defined as no progression (NP), TP, or PP. Supervised machine learning was utilized using a 500-tree random forest (RF) classification model with TP or PP as the outcome. Variable importance analysis was conducted by calculating the out-of-bag errors with multiple bootstrapped data sets. The most prognostic features were selected using the RF importance scores. Thirty-six patients were screened for inclusion: 9 were excluded due to no T2 lesion (RC ROI only). Of the remaining 27 patients: 10 had NP, 11 had TP, and 6 had PP. Thirty-nine texture features, plus lesion volume and mean lesion intensity (for a total of 41 variables per time point) were calculated and included in the model. Of the 10 most prognostic features, 6 were from D10, suggesting that prognostic changes in the underlying lesion microenvironment are occurring within the first 10 fractions of treatment. The model selected GLSZM high gray-level zone emphasis (HGZE) D10, IBSI code 5GN9, as the most prognostic feature. The receiver operator characteristic (ROC) area under the curve (AUC) for GLSZM HGZE D10 was 0.94 (95% CI = 0.81-1.00). Delta radiomic features extracted from MR-Linac imaging may predict between PP and TP in GBM patients during treatment, which is earlier than current methods. This could allow physicians to adapt/intensify treatment in real time for poorly responding patients. Future directions include analysis with a larger patient cohort and with additional MRI contrasts (MR-Linac multiparametric MRI).

Pattern Analysis of Daily Lesion Volume Trajectories for Early Prediction of Glioblastoma Progression During MR-Linac Radiotherapy

Distinguishing between true progression (TP) and pseudoprogression (PP) post-radiotherapy (RT) is of paramount importance for treatment management of patients with glioblastoma (GBM). MR-Linac systems allow for daily monitoring of tumor changes throughout the course of RT. We hypothesized that the patterns of tumor volume change during RT may enable early prediction of treatment response. Using an IRB-approved prospective cohort of GBM patients undergoing 30 fractions of chemoRT to 60 Gy on a 0.35T MR-Linac, tumor/edema (tumor lesion) regions of interest (ROI) were contoured on daily T2-weighted treatment set-up scans. The obtained tumor lesion (TL) volume changes during treatment were smoothed with a moving average Gaussian window over time. Non-negative Matrix Factorization (NMF) was applied to the data matrix D (N x F), containing the trajectories in its rows for each patient, where N is the number of patients analyzed and F is the number of fractions. NMF represents D as a linear combination of three temporal (hidden) patterns and their weights in each individual trajectory. The same analysis was performed for ΔD, containing the changes in volumes with reference to the first fraction. The calculated weights were scaled in [0, 1], expressed as probabilities (by ℓ1-normalization) and used as features in Linear Discriminant Analysis (LDA). The LDA model was trained to differentiate between no progression (NP), PP and TP, and assessed by leave-one-subject-out cross-validation. Thirty-six patients were screened for inclusion: 9 were excluded due to no T2 lesion (resection cavity only). Of the remaining 27 GBM patients analyzed, 10 had no tumor growth on first post-RT diagnostic MRI, 6 were determined to have PP based on regression or long-term stability of findings, and 11 had TP due to continued progression of disease past 6 months, rapid patient death from disease, or tissue sampling showing active malignancy. With the use of only 2 features, LDA achieved an overall accuracy of 70.4% classifying correctly: 6 (60%), 4 (67%), and 9 (82%) patients with NP, PP, and TP, respectively. The temporal NMF patterns (monotonous decrease, rapid increase during the third part of the treatment, etc.) indicate that there is enough signal to classify patients' response based on the pattern tumor volume changes during RT. We identified tumor dynamics' patterns during RT, indicative of differential behavior of tumor growth between TP and PP. Although with a limited number of patients, these initial results suggest that tumor volume changes during treatment may provide early markers of treatment response. This could allow physicians to adapt/intensify treatment in real time for poorly responding patients. Next steps include automating the process of real-time tumor volume monitoring by incorporating a deep learning solution for automatic volume delineation on daily treatment set-up scans.

Magnetic resonance fingerprinting in multiple sclerosis

BackgroundIn this cross sectional study, we used MRF to investigate tissue properties of normal-appearing white matter, gray matter, and lesions in relapsing remitting MS (n = 21), secondary progressive MS (n = 16) and healthy controls (n = 9). A FISP-based MRF sequence was used for acquisition, imaging time 5 min 15 s. MRF T1 and T2 relaxation times were measured from lesional tissue, normal-appearing frontal white matter, corpus callous, thalamus, and caudate. Differences between healthy controls and MS were examined using ANCOVA adjusted for age and sex. Spearman rank correlations were assessed between T1 and T2 relaxation times and clinical measures. ObjectivesTo examine brain T1 and T2 values using magnetic resonance fingerprinting (MRF) in healthy controls and MS. MethodsThe subjects included 21 relapsing-remitting (RR) MS, 16 secondary progressive (SP) MS, and 9 age- and sex-matched HC without manifest neurological disease participating in a longitudinal MRI study. A 3T/ FISP-based MRF sequence was acquired. Regions of interest were drawn for lesions and normal appearing white matter. ANCOVA adjusted for age and sex were used to compare the groups with significance set at 0.05. ResultsA step-wise increase in T1 and T2 relaxation times was found between healthy controls, relapsing remitting MS, and secondary progressive MS. Significant differences were found in T1 and T2 between MS and healthy controls in the frontal normal-appearing white matter, corpus callosum, and thalamus (p < 0.04 for all). Significant differences in T1 and T2 between RR and SPMS were found in the frontal normal-appearing white matter and T2 lesions (p < 0.02 for all). T1 relaxation from the frontal normal-appearing white matter correlated with the Expanded Disability Status Scale [ρ = 0.62, p < 0.001], timed 25 foot walk (ρ = 0.45, p = 0.01), 9 hole peg test (ρ = 0.62, p < 0.001), and paced auditory serial addition test (ρ = −0.4, p = 0.01). ConclusionThese results suggest that MRF may be a clinically feasible quantitative approach for characterizing tissue damage in MS.

Pretreatment Neurofilament Light Chain Serum Levels, Early Disease Severity, and Treatment Response in Pediatric Multiple Sclerosis.

High disease activity and frequent therapy failure in pediatric multiple sclerosis (MS) make prognostic biomarkers urgently needed. We investigated whether serum neurofilament light chain (sNfL) levels in treatment-naive pediatric patients with MS are associated with early disease severity and indicate treatment outcomes. A retrospective cohort study of patients seen in the Göttingen Center for MS in Childhood and Adolescence, Germany. Inclusion criteria were MS diagnosis according to the McDonald criteria, MS onset <18 years, and available pretreatment serum sample. sNfL levels were analyzed using a single-molecule array assay. Associations with clinical and MRI evidence of disease severity at sampling were evaluated using the Spearman correlations and nonparametric tests for group comparisons. Correlations between pretreatment sNfL and annualized relapse and new T2 lesion rate on first-line therapy, and odd ratios for switch to high-efficacy therapy were assessed. A total of 178 patients (116 women [65%]) with a mean sampling age of 14.3 years were included in the study. Pretreatment sNfL levels were above the ≥90th percentile reported for healthy controls in 80% of patients (median 21.1 pg/mL) and correlated negatively with age, but no correlation was seen with sex, oligoclonal band status, or body mass index. High pretreatment sNfL levels correlated significantly with a high number of preceding relapses, a shorter first interattack interval, a high T2 lesion count, and recent gadolinium-enhancing lesions. Of interest, sNfL levels reflected more strongly MRI activity rather than clinical activity. Pretreatment sNfL levels also correlated significantly with the relapse rate and occurrence of new/enlarging T2 lesions while on first-line injectable therapy. Odds of future therapy escalation increased from 0.14 for sNfL below 7.5 pg/mL to 6.38 for sNfL above 15 pg/mL. In patients with a recent relapse, higher sNfL levels were associated with poorer recovery 3 months after attack. The results of this study have 3 important implications: First, pretreatment sNfL levels are a valuable biomarker for underlying disease activity in pediatric patients with MS. Second, pretreatment sNfL levels in pediatric patients with MS have a predictive value for the response to first-line therapy and the necessity of future therapy escalation. Third, high sNfL levels during a relapse are associated with poor recovery in this age group.

Association of MRI leptomeningeal enhancement with disability worsening in progressive multiple sclerosis: A clinical and post-mortem study

Background: Leptomeningeal enhancement (LME) has been described as a biomarker of meningeal inflammation in multiple sclerosis (MS). Objective: The aim of this study was to (1) assess if LME is predictive of disability worsening in progressive MS (pMS) patients and (2) investigate the pathological substrates of LME in an independent post-mortem MS series. Methods: In total, 115 pMS patients were imaged yearly with 1.5T MRI, using post-contrast CUBE 3D FLAIR for LME detection. Endpoint: to identify the baseline variables predictive of confirmed disability worsening (CDW) at 24 months follow-up. Post-mortem, inflammation, and structural changes of the leptomeninges were assessed in 12 MS/8 control brains. Results: LME (27% of patients at baseline) was associated with higher EDSS and lower brain volume (nBV). LME was unchanged in most patients over follow-up. LME at baseline MRI was independently associated with higher risk of 24 months CDW (HR 3.05, 95% CI 1.36–6.84, p = 0.007) in a Cox regression, including age, nBV, T2 lesion volume, high-efficacy treatments, and MRI disease activity. Post-mortem, focal structural changes (fibrosis) of the leptomeninges were observed in MS, usually associated with inflammation (Kendall’s Tau 0.315, p < 0.0001). Conclusions: LME is frequently detected in pMS patients using 1.5T MRI and is independently predictive of disability progression. LME could result from both focal leptomeningeal post-inflammatory fibrosis and inflammation.

Escalation Versus Induction/High-Efficacy Treatment Strategies for Relapsing Multiple Sclerosis: Which is Best for Patients?

After more than 2decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36-72 mg/m2, followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment.

External validation of the pediatric International IgA Nephropathy Prediction Tool in a central China cohort.

This study aimed to externally validate the pediatric International IgA Nephropathy (IgAN) Prediction Tool updated from the adult IgAN Prediction Tool. 439 children with biopsy-confirmed idiopathic IgAN were enrolled in this external validation study. The primary outcome was a 30% decline in eGFR or end-stage kidney disease. We evaluated the discrimination using Harrell's C-index, the receiver operating characteristic (ROC) curve, and Kaplan-Meier curves for four risk groups (< 16th [low risk], ∼16 to < 50th [intermediate risk], ∼50 to < 84th [high risk], and ≥ 84th percentiles [highest risk] of linear predictor). Calibration was assessed using calibration plots. The median follow-up time of the 439 patients was 4.5 (2.7-6.8) years, and 27 patients reached the primary outcome. Compared with the reported cohorts, our cohort was more contemporary, with milder proteinuria at biopsy, and had lower proportions of S1 and T1 lesions. Harrell's C-index and area under the ROC curve at 5years were < 0.7 for both the models with and without race. The Kaplan-Meier curves of the risk groups were not well separated for the two models, only separated completely between the highest-risk group and the others for the model without race. The two models generally overestimated the risk of the primary outcome, CONCLUSION: The model without race could accurately distinguish the highest-risk patients from patients with low, intermediate, and high risk for kidney progression. Discrimination and calibration for the full model with or without race were unsatisfactory in this contemporary cohort in central China.

Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOS open-label extension

Background: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS). Objective: Further characterize efficacy and safety of ofatumumab in RMS. Methods: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021. Results: In the efficacy set (n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04–0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter “no evidence of disease activity” criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set (n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified. Conclusion: Ofatumumab has a favorable longer-term benefit–risk profile in RMS. Trial registry: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114