Early Active Lesions Research Articles

Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study.

Numerous clinical trials of sirolimus, an inhibitor of mechanistic/mammalian target of rapamycin complex 1, for the treatment of vascular malformations have been conducted. However, aside from lymphatic malformations, the efficacy of sirolimus for venous and capillary malformations has not been established. Moreover, no generalized venous or capillary malformations have been treated with topical sirolimus. To evaluate the safety and efficacy of topical sirolimus for venous and capillary malformations and to compare the efficacy of topical and systemic sirolimus therapy, an open-label single-arm pilot study with 0.2% sirolimus gel was conducted from July 19, 2019, to January 30, 2020, in four patients diagnosed with different vascular malformations (blue rubber bleb nevus syndrome, common venous malformation, phakomatosis pigmentovascularis type IVb, and angiokeratoma in Fabry disease). The primary endpoint was the safety evaluation of sirolimus gel. The main secondary endpoint was the improvement rate evaluated by the Central Judgment Committee at 12 weeks using photographs. No adverse events were observed. Blood sirolimus was not detected in any patient. Two patients (50%) had mild improvement, and the remaining two patients (50%) showed no change after 12 weeks of treatment. Blue rubber bleb nevus syndrome, a generalized venous malformation, showed the greatest response. In conclusion, 0.2% sirolimus gel was found to be as clinically effective as systemic sirolimus treatment in patients with venous and capillary malformations and more effective for early active lesions, even systemic venous malformations.

Iron Heterogeneity in Early Active Multiple Sclerosis Lesions.

ObjectiveMultiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown.MethodsWe used synchrotron X‐ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients.ResultsImmunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17–127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3–64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = −40 to −14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X‐ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron.InterpretationIron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron‐sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498–510

Efficacy of Sealing Proximal Early Active Lesions: An 18-Month Clinical Study Evaluated by Conventional and Subtraction Radiography

This study assessed the efficacy of sealing proximal lesions on adult patients using a split-mouth design. Eighty-two 15- to 39-year-olds from the Dental Faculties in Copenhagen and Bogotá participated, each having 2 or more proximal lesions in the following radiographic stages: (1) lesion restricted to the outer half of enamel; (2) lesion from the inner half of enamel including the enamel dentine junction, and (3) lesion restricted to the outer third of dentine. Standardized geometrically aligned baseline and follow-up radiographs were obtained. One randomly selected lesion (test) in each patient was sealed with 1 of 2 resins. The patients were instructed to floss all the proximal lesions 3 times per week. The baseline to 18 months difference in caries lesion progression status was assessed using 3 methods: (1) radiographs were independently assessed visually; (2) radiographs were read in pairs, and (3) using subtraction radiography of digitized images. A total of 72 subjects finished the study (12.2% dropout). The compliance concerning flossing was poor (15%). For the repeated examinations kappa was 0.84 for the visual examination, 0.44 for the paired readings and 0.84 for the subtraction examination. Two test lesions and 1 control lesion were restored. For the independent radiograph assessment method 10 and 26% progressed in the test and control group, respectively (p > 0.05); with the paired radiograph method the corresponding data were 22% in the test and 47% in the control groups (p < 0.01). By subtraction radiography 44% of the test group and 84% of the control were judged to have progressed (p < 0.001). The sealing technique was superior to instructing patients to floss, and subtraction radiography appeared to be the most sensitive method for assessing lesion progression.

Identification of glial cell proliferation in early multiple sclerosis lesions.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to destruction of myelin sheaths. The patterns of cell proliferation in the early course of the disease are largely unknown. The present study used immunohistochemical identification of proliferating glial cells in stereotactic brain biopsy material of eight patients with early chronic MS. Double-labelling with the proliferation marker MIB-1 detected proliferating oligodendrocytes (MOG), astrocytes (GFAP) and microglia/macrophages (Ki-M1P). The majority of proliferating cells were macrophages/microglia when compared with oligodendrocytes (P > 0.005) or astrocytes (P > 0.0005); only a minor proportion of microglia/macrophages, however, proliferated in situ. Astrocytic and oligodendroglial proliferation was sparse to absent and showed significant variations between different patients. There were statistically significant differences when comparing the amount of proliferation between lesions of different demyelinating activity: highest numbers of proliferating cells were found in early active lesions compared with demyelinated and early remyelinated lesions (P > 0.05) or the periplaque white matter (P > 0.01). MOG-positive oligodendrocytes proliferated occasionally in the early stages of lesion formation; this proliferation occurred in four cases but was independent of the stage of the disease. Since MOG is expressed by mature oligodendrocytes, and not by immature precursors, this might suggest a potential role for the proliferation of mature surviving oligodendrocytes with subsequent remyelination.