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Objective: An earlier follow-up study from the CogEx rehabilitation trial showed little change in symptoms of depression, anxiety and psychological distress during the first COVID-19 lockdown compared to pre-pandemic measurements. Here, we provide a second follow-up set of behavioral data on the CogEx sample. Methods: This was an ancillary, longitudinal follow-up study in CogEx, a randomized controlled trial of exercise and cognitive rehabilitation in people with progressive MS involving 11 centres in North America and Europe. Only individuals impaired on the Symbol Digit Modalities Test (SDMT) were included. Participants repeated the COVID Impact survey administered approximately a year later and completed self-report measures of depression, anxiety and MS symptoms that had been obtained at the trial baseline and during the first COVID Impact survey. Participants who completed the second COVID Impact follow-up were included. To identify predictors of the participants’ ratings of their mental and physical well-being, step-wise linear regression was conducted. Results: Of the 131 participants who completed the first COVID impact survey, 74 participants completed the second follow-up survey (mean age 52 (SD = 6.4) years, 62.2% female, mean disease duration 16.4 (SD = 9.0) years, median EDSS 6.0). Pandemic restrictions prevented data collection from sites in Denmark and England (n = 57). The average time between measurements was 11.4 (SD = 5.56) months. There were no significant differences in age, sex, EDSS, disease course and duration between those who participated in the current follow-up study (n = 74) and the group that could not (n = 57). One participant had COVID in the time between assessments. Participants now took a more negative view of their mental/psychological well-being (p = 0.0001), physical well-being (p = 0.0009) and disease course (p = 0.005) compared to their last assessment. Depression scores increased on the HADS-depression scale (p = 0.01) and now exceeded the clinically significant threshold of ≥ 8.0 for the first time. Anxiety scores on the HADS remained unchanged. Poorer mental well-being was predicted by HADS depression scores (p = 0.012) and a secondary-progressive disease course (p = 0.0004). Conclusions: A longer follow-up period revealed the later onset of clinically significant depressive symptoms on the HADS and a decline in self-perceptions of mental and physical well-being associated with the COVID-19 pandemic relative to the first follow-up data point. Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated.

Objectives: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS). Methods: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery (“treatment approach,” (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery (“conservative approach,” (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire. Results: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6–10.6, p = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4–7.9 p = 0.007). We found no major development abnormalities in children. Discussion: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.

Background: Previous studies demonstrated an association between motor and cognitive performance in multiple sclerosis (MS). However, disease-related brain damage might represent a common substrate to both phenomena, which was not considered before. Objective: Aim of this study is to investigate whether the association between cognition and motor function is beyond structural damage in patients with MS. Methods: Eighty-one healthy controls and 106 relapsing–remitting (RR) MS patients underwent a 3.0T MRI with quantification of T2-lesion volumes, T1-lesion volumes and normalized brain volumes. A functional examination [Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25FW) and Expanded Disability Status Scale] and a neuropsychological evaluation (Brief Repeatable Battery of Neuropsychological Tests) were also administered. Association between demographic, clinical, cognitive, MRI and functional measures were analysed with univariate analyses and hierarchical linear regression. Results: In RRMS patients, Spatial Recall Test and Symbol Digit Modalities Test were positively correlated with 9-HPT (p < 0.001) and T25FW (p ≤ 0.035); Paced Auditory Serial Addition Test (PASAT) correlated with 9-HPT (p ≤ 0.009). 9-HPT and T25FW were significantly associated with normalized brain volumes (p ≤ 0.016), T2- and T1-lesion volumes (p ≤ 0.009). Hierarchical regression models selected age and normalized deep gray matter volume as predictors of T25FW (adjusted-R2 = 0.109). Younger age, female sex, higher normalized gray matter volume and higher PASAT 2″ scores predicted higher 9-HPT scores (adjusted-R2 = 0.337). Conclusions: In RRMS patients, deficit in information processing speed and executive function may contribute to hand motor dysfunction beyond the effect of structural disease-related burden, supporting the integration of motor and cognitive assessment in clinical settings.

Background Altered callosal integrity has been associated with motor deficits in patients with multiple sclerosis (MS), but its contribution to disability has, to the knowledge of the authors, not been investigated by using multiparametric MRI approaches. Purpose To investigate structural and functional interhemispheric MRI substrates of global disability at different milestones and upper limb motor impairment in MS. Materials and Methods In this cross-sectional study, healthy control patients and patients with MS (between January 1, 2008, and December 31, 2016) were retrospectively selected from our hospital database. Clinical assessment included Expanded Disability Status Scale (EDSS), nine-hole peg test, and digital finger tapping test. By using structural and resting-state functional MRI sequences, probabilistic tractography of hand corticospinal tract fibers, and transcallosal fibers between hand-motor cortices (hereafter, referred to as hand-M1), supplementary motor areas (SMAs), premotor cortices (PMCs), and voxel-mirror homotopic connectivity (VMHC) were analyzed. Random forest analyses identified the MRI predictors of clinical disability at different milestones (EDSS scores of 3.0, 4.0, 6.0) and upper limb motor impairment (nine-hole peg test and finger tapping test z scores < healthy control patients 5th percentile). Results One-hundred thirty healthy control patients (median age, 39 years; interquartile range, 31-50 years; 70 women) and 340 patients with MS (median age, 43 years; interquartile range, 33-51 years; 213 women) were studied. EDSS 3.0 predictors (n = 159) were global measures of atrophy and lesions together with damage measures of corticospinal tracts and transcallosal fibers between PMCs and SMAs (accuracy, 86%; P = .001-.01). For EDSS 4.0 (n = 131), similar predictors were found in addition to damage in transcallosal fibers between hand-M1 (accuracy, 89%; P = .001-.049). No MRI predictors were found for EDSS 6.0 (n = 70). Nine-hole peg test (right, n = 161; left, n = 166) and finger tapping test (right, n = 117; left, n = 111) impairments were predicted by damage in transcallosal fibers between SMAs and PMCs (accuracy range, 69%-77%; P = .001-.049). VMHC abnormalities did not explain clinical outcomes. Conclusion Structural, not functional, abnormalities at MRI in transcallosal premotor and motor white matter fibers predicted severity of global disability and upper limb motor impairment in patients with multiple sclerosis. The informative role of such predictors appeared less evident at higher disability levels. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Barkhof and Pontillo in this issue.

Objective: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. Background: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. Methods: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18–65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45–48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. Results: A total of 242 patients with migraine received at least one dose of erenumab 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-preventive medication classes. From baseline to Weeks 45–48, erenumab treatment reduced MMD by 4.3±5.3(mean±SD) in patients with HFEM, and MHD by 12.8±8.9 (mean±SD) in subjects with CM. VAS and HIT-6scores were decreased by 1.8±1.9 (mean±SD) and 12.3±11 (mean±SD) in HFEM, and by 3.0±2.2 (mean±SD) and 13.1±11.2 (mean±SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0–13.0) to 5 (IQR 2.0–8.0) in HFEM and from 20.0 (IQR 15.0–30.0) to 6.0 (IQR 3.8–10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52–19.41; p=0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03–8.7; p=0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05–1.20; p=0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15–0.87; p=0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64–0.92; p=0.004). Conclusions: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Aim: To investigate the transcriptional changes induced by Fingolimod (FTY) in T cells of relapsing remitting multiple sclerosis patients. Patients & methods: Transcriptomic changes after 6 months of FTY therapy were evaluated on T cells from 24 relapsing remitting multiple sclerosis patients through RNA-sequencing, followed by technical validation and pathway analysis. Results: Among differentially expressed genes, CX3CR1 and CCR7 resulted strongly up- and downregulated, respectively. Two relevant genes were validated with quantitative PCR and we largely confirmed findings from two previous microarray-based studies with similar design. Pathway analysis pointed to an involvement of processes related to immune function and cell migration. Conclusion: Our data support the evidence that FTY induces major transcriptional changes in genes involved in immune response and cell trafficking in T lymphocytes.

Background and purpose A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real-life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers. Methods All consecutive adult patients with CM diagnosis with the clinical indication for galcanezumab were considered. We collected patients' baseline characteristics, monthly headache days, monthly painkiller intake, migraine clinical characteristics, and disability scale scores during a 1-month run-in period (baseline) and the first 3 months of therapy. Possible predictive factors of treatment were considered. Results A total of 156 patients (82.4% female, aged 47.3 +/- 12.3 years) were enrolled. The 65 (41.7%) patients with a consecutive >= 50% response rate (RR) in the 3 months of therapy presented a lower body mass index (p = 0.004) and more frequently presented unilateral migraine pain (p = 0.002) and good response to triptans (p = 0.003). Persistent conversion from CM to episodic migraine was observed in 55.8% (87/156) of patients. They more frequently presented a good response to triptans (p = 0.003) and unilateral pain (p = 0.046). At baseline, 131 of 156 (83.9%) patients presented medication overuse (MO). Of these, 61.8% (81/131) no longer displayed MO consistently during the 3 months. These patients were more frequently responders to triptans (p = 0.002) and less frequently suffered from gastrointestinal comorbidity (p = 0.007). Conclusions Unilateral pain, good response to triptans, and normal weight may be associated with a persistent positive response in the first 3 months of therapy with galcanezumab in CM patients.

Background Monoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients. Methods This observational longitudinal cohort study was conducted at 10 Italian headache centres. Consecutive adult patients were followed-up for three months (F-UP1–3) after discontinuation of a one-year erenumab/galcanezumab treatment. The primary endpoint was the change in F-UP MMDs. Secondary endpoints included variation in pain intensity (Numerical Rating Scale, NRS), monthly acute medication intake (MAMI), and HIT-6 scores. We also assessed from F-UP1 to 3 the ≥50% response rate, relapse rate to CM, and recurrence of Medication Overuse (MO). Results We enrolled 154 patients (72.1% female, 48.2 ± 11.1 years, 107 CM, 47 HFEM); 91 were treated with erenumab, 63 with galcanezumab. From F-UP1 to F-UP3, MMDs, MAMI, NRS, and HIT-6 progressively increased but were still lower at F-UP3 than baseline (Friedman’s analysis of rank, p p = .032). Of the 84 baseline CM patients who had reverted to episodic migraine, 28 (33.3%) relapsed to CM at F-UP1, 35 (41.7%) at F-UP2, 39 (46.4%) at F-UP3. Of the 64 baseline patients suffering of medication overuse headache ceasing MO, 15 (18.3%) relapsed to MO at F-UP1, 26 (31.6%) at F-UP2, and 30 (42.3%, 11 missing data) at F-UP3. Lower MMDs, MAMI, NRS, and HIT-6 and higher response rate in the last month of therapy characterized patients with ≥50% response rate at F-UP1 and F-UP3 (Mann-Whitney U test; consistently p Conclusion Migraine frequency and disability gradually increased after mAbs anti-CGRP interruption. Most patients did not relapse to MO or CM despite the increase in MMDs. Our data suggest to reconsider mAbs anti-CGRP discontinuation.

Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. Objective: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. Methods: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson’s correlation at single subject level. Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer’s disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β = –0.804; p = 0.016). Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n=36) and relapsed (n=27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.

Introduction Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD. Methods 24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic. Results DLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB. Conclusions DLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD.

A 34-year-old pregnant woman at 28 gestational weeks was diagnosed with a brain tumor after experiencing a generalised seizure. After completion of antenatal fetal lung maturation, she underwent an osteoplastic craniotomy parietal on the left side and a microsurgical partial tumor resection under general anaesthesia. With a histology of a diffuse astrocytoma and the postoperative stable amount of residual tumor on follow-up imaging, the pregnancy proceeded until 37 gestational weeks. A healthy baby boy was delivered by elective caesarean section. An awake craniotomy for removal of the residual tumor was planned two weeks later, followed by adjuvant treatment (combined radio-/chemotherapy). A multidisciplinary approach, combined with appropriate timing and a transparent and empathic communication, was able to create the most effective tailored management and optimise maternal and neonatal outcomes.

Background and Objectives:In multiple sclerosis (MS), functional networks undergo continuous reconfiguration and topography changes over the disease course. Here, we aimed to investigate functional networks topography abnormalities in MS and their association with disease phenotype, clinical and cognitive disability, and structural MRI damage.Methods:This is a multi-centre cross-sectional study. Enrolled subjects performed MRI, neurological and neuropsychological assessment. Network topography was assessed on resting state fMRI data using degree centrality, which counted the number of functional connections of each grey matter voxel with the rest of the brain. SPM12 age-, sex-, scanner-, framewise displacement and grey matter volume adjusted ANOVA and multivariable regressions were employed (pResults:We enrolled 971 patients with MS (624 females; mean age=43.1 ±11.8 years; 47 clinically isolated syndrome [CIS], 704 relapsing-remitting [RRMS], 145 secondary progressive [SPMS] and 75 primary progressive [PPMS]) and 330 healthy controls (186 females; mean age=41.2 ± 13.3 years). Patients with MS showed reduced centrality in the salience and sensorimotor networks as well as increased centrality in the default mode network vs controls (pvs controls and in RRMS vs CIS (pvs RRMS (pvs controls (pvs cognitively preserved patients (pDiscussion:Patients with MS presented with reduced centrality in the salience and primary sensorimotor networks and increased centrality in the default mode network. Centrality abnormalities were specific for different disease phenotypes and associated with clinical and cognitive disability, hence suggesting that voxel-wise centrality analysis may reflect pathological substrates underpinning disability accrual.

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.

Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking. Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS. Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up. Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models. Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective). Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis. Graphical Abstract

Background Overweight and obese patients with solid tumors receiving anti-programmed cell death-1 (PD-1)/PD-ligand-1(PD-L1) immune checkpoint inhibitors exhibit improved survival and higher risk of immune-related adverse events (irAEs) than those with a normal body mass index (BMI). In classic Hodgkin lymphoma (cHL), the impact of BMI on survival and immune-related toxicity is unknown. We evaluated for the first time associations of BMI with survival and irAEs in patients with relapsed/refractory (RR)-cHL undergoing PD-1 blockade. Methods Data from a multicenter study on 133 patients treated with the anti-PD1 antibody nivolumab (July 2015–December 2016) were retrieved from a prospective database. Progression-free (PFS), overall survival (OS), incidence and severity of irAEs according to BMI categories were estimated by Kaplan–Meier method, landmark-analyses and Cox regressions. Results Patients, mostly males (63%, n = 84) with a median age of 35 years (range, 15–82), advanced stage (75%), B symptoms (63%), bulky disease (24%), a median of 4 previous treatments (range, 1–9), received a median of 18 nivolumab doses (range, 1–57). No statistically significant differences across BMI subgroups emerged as to PFS, with 1-year rates of 67.1% for both normal weight (n = 66; 49.6%) and overweight (n = 31; 23.3%) patients. Underweight (n = 12; 9%) and obese (n = 24; 18%) patients had a 1-year PFS of 54.5% and 49%, respectively. In survival analyses, BMI either as a continuous (P = 0.5) or categorical (P for trend = 0.63) variable failed to associate with PFS. Response rates and time-to-response did not cluster in any BMI subset. No BMI-related differences in OS emerged across normal, overweight and obese patients but underweight patients had the worst survival. Occurrence of irAEs of whatever severity did not statistically associate with BMI. Conclusions In patients with RR-cHL receiving nivolumab, no statistically significant differences emerged in response rates, PFS and OS across BMI categories of normal weight, overweight and obese. Overweight/obese patients did not display an increased risk of irAEs. The exquisite sensitivity to anti-PD-1 antibodies, the unique cytokine milieu and effector pathways triggered by nivolumab in cHL, may represent biologic ‘equalizers’ counteracting the immunoregulatory effects of adiposity. Differently from solid tumors, BMI is not associated with treatment efficacy and immune-related toxicity and does not represent a predictive tool for PD-1-targeted immunotherapies in cHL.

To estimate the prevalence of women who were admitted to health facilities with abortion-related complications who reported feeling anxious/stressed during their stay, and to identify sociodemographic, facility, and abortion-related characteristics associated with self-reported experience of anxiety/stress.We used data from four countries in Eastern and Southern Africa (Kenya, Malawi, Mozambique, and Uganda) collected from 2017-2018 as part of the World Health Organization (WHO) Multi-Country Survey on Abortion-related morbidity (MCS-A). Information was extracted from women's medical records and their participation in audio computer-assisted self-interviews (ACASI). Based on a question in the ACASI, "Did you encounter any anxiety or stress during your hospital stay?", the percentage of women who self-reported feeling anxious/stressed during their facility stay was calculated. Generalized estimating equations were used to identify the determinants of anxiety/stress following a hierarchical approach whereby potential determinants were grouped from most distal to most proximal and analyzed accordingly.There were 1254 women with abortion-related complications included in the analysis, of which 56.5% self-reported that they felt anxious/stressed during their facility stay. We found evidence that lower socioeconomic status, lower levels of education, no previous childbirth, no previous abortion, higher gestational age at abortion, and use of unsafe methods of abortion were independent determinants of self-reporting anxiety/stress.Action should be taken to reduce experience of anxiety/stress among women attending facilities for postabortion complications, including reducing the number of women experiencing abortion-related complications by improving access to safe abortion. This issue warrants further study using more comprehensive and validated tools to understand the levels and drivers of anxiety/stress self-reported by women attending facilities with abortion-related complications.

Decidualization is the process of endometrial change in pregnancy, a phenomenon that can involve also ovarian endometriomas. However, the frequency of this event remains unknown. In addition, there is no evidence on the decidualization of deep invasive endometriosis (DIE). To shed more light on this issue, we prospectively recruited women with ovarian endometriomas or DIE who underwent IVF. They were subsequently excluded if they did not become pregnant or if they had a miscarriage. The evaluation was repeated in 5 time points during pregnancy and post-partum. The primary outcome was the rate of decidualized endometriomas at 11-13 weeks’ gestation. Data from 45 endometriomas and 15 nodules were available for data analyses. At the 11-13 weeks’ ultrasound, endometriomas’ decidualization was observed in seven cases, corresponding to 16% (95%CI: 8-29%). Subsequent assessments in pregnancy failed to identify any additional case. DIE also underwent significant changes during pregnancy. An increase in mean diameter (at least 50%), an increase in color score or both were documented in seven, eight and five cases, respectively. In conclusion, decidualization of ovarian endometriomas in IVF pregnancies is common. DIE may also undergo decidualization, but further evidence is needed for a robust and shared definition of this process.

Chloracne, also known as metabolizing acquired dioxin-induced skin hamartomas (MADISH), is a rare disfiguring disease related to dioxin exposure. There is a paucity of literature on the clinical manifestations and pathogenesis of chloracne/MADISH. The aim of this study was to assess the clinical features of this very unusual acneiform eruption and to explore the pathogenesis of the disease. This was a retrospective, observational report study was conducted on five patients belonging to the same nuclear family (father, mother and three children) and a relative (father's brother) living in the same house. Histopathological, immunohistochemical, laboratory and toxicological analyses were performed for all patients. The results suggest that CYP1A1 in human skin is a diagnostic biomarker in chloracne, and was positive for all the patients in our sample. Tetrachlorodibenzo-p-dioxin is the most investigated dioxin responsible for chloracne; however, several other agonists, whether dioxin-like or not, can activate the aryl hydrocarbon receptor. To our knowledge, this Italian case series is the first study to suggest polychlorinated biphenyls as a possible cause of an overstimulation of aryl hydrocarbons causing the consequent acneiform eruption.

Objective:Insecurity disrupts health systems, quality of care and increases delays in obtaining services. This paper examines the relationship between insecurity and the quality of care provided for abortion complications in high-volume hospitals in the Democratic Republic of Congo (DRC). Methods:Using the WHO Multi-Country Survey on Abortion complications, we analysed data for 1007 women who received care in 24 facilities in DRC. For inputs of care, we calculated the percentage of facilities in secure and insecure areas meeting 12 readiness criteria for infrastructure and capability. For process and outcomes of care, we estimated the association between security and 8 indicators using generalised estimating equation models.Findings:Facilities in secure areas were more likely to report functioning electricity (93.3% versus 66.7%), availability of obstetrician 24/7 (42.9% versus 28.6%) and the ability to offer several short acting contraceptives (83.3% versus 57.1%). However, a higher percentage of facilities in insecure areas reported the availability of a telephone or radio (100% versus 80.0%). Women in insecure areas appeared more likely to experience poor quality clinical care overall than women in secure areas [adjusted odds ratio (aOR)=2.56, 95% confidence interval (CI)=1.13-5.82), p-value=0.03]. However, there was no association between security and incomplete medical records (p=0.20), use of dilatation and curettage (D&C) (p=0.84), women reporting poor experience of care (p=0.22), satisfaction with care (p=0.25) and severe maternal outcomes (p=0.56). There was weak evidence of an association between security and non-receipt of contraceptives (p=0.07), with women in insecure areas 70% less likely to report no contraception (aOR=0.31, 95% CI=0.09-1.09). Use of D&C was high in secure (41%) and insecure areas (60%). Conclusion:In this study, quality of care does not seem to be very different in secure and insecure areas in DRC, except for some key infrastructure, supply, and human resources elements. The frequent use of D&C for uterine evacuation, the lack of good record keeping and the lack of contraceptive should be urgently addressed.

OBJECTIVE: Despite evidence of acute and long-term consequences of suboptimal experiences of care, standardized measurements across countries remain limited, particularly for postabortion care. We aimed to determine the proportion of women reporting negative experiences of care for abortion complications, identify risk factors, and assess the potential association with complication severity. METHODS: Data were sourced from the WHO Multi-Country Survey on Abortion for women who received facility-based care for abortion complications in 11 African countries. We measured women's experiences of care with eight questions from an audio computer-assisted self-interview related to respect, communication, and support. Multivariable generalized estimating equations were used for analysis. RESULTS: There were 2918 women in the study sample and 1821 (62%) reported at least one negative experience of postabortion care. Participants who were aged under 30 years, single, of low socioeconomic status, and economically dependent had higher odds of negative experiences. Living in West or Central Africa, rather than East Africa, was also associated with reportedly worse care. The influence of complication severity on experience of care appeared significant, such that women with moderate and severe complications had 12% and 40% higher odds of reporting negative experiences, respectively. CONCLUSION: There were widespread reports of negative experiences of care among women receiving treatment for abortion complications in health facilities. Our findings contribute to the scant understanding of the risk factors for negative experiences of postabortion care and highlight the need to address harmful provider biases and behaviors, alleviate health system constraints, and empower women in demanding better care.

Objectives To evaluate the pubocervical fascia (PF) in patients with pelvic organ prolapse (POP) using 3-dimensonal endovaginal ultrasonography (EVUS) and to correlate the PF appearance with both pelvic examination and intraoperative findings during ultrasonographic robotic-assisted laparoscopic sacrocervicopexy and pubocervical fascia reconstruction (u-RALS-PFR). Methods A retrospective analysis was performed in 120 women with symptomatic POP. Preoperative evaluation was done using EVUS. We identified areas of PF weakness based on pelvic examination as hypoechoic and hyperechoic defects (HHD) between the bladder and vagina. Study measurements included distance from the HHD to the pubic symphysis, HHD to the bladder neck, HHD to the posterior bladder wall, and hypoechoic-hyperechoic area. We correlated these metrics with the respective POP-Q stages and findings during u-RALS-PFR. Results Using the quantitative measures during EVUS, we found a significant association between mean HHD (2.7 cm) and POP-Q stage III, and between HHD and number of plications performed during surgery. The larger the HHD, the more severe the POP-Q stage of the anterior compartment of the vaginal wall; thus, more plications were performed on the PF (7-12 plications) during robotic sacrocervicopexy, and consequently the anterior arm of the Y-mesh was significantly trimmed (6-8 cm). Conclusion HHD obtained by EVUS was associated with severe POP-Q stage III and seemed to correlate with the number of plications during robotic sacrocervicopexy. Performing these plications on the PF significantly decreased the length of the anterior vaginal mesh needed for the procedure. These findings may open new applications for preoperative ultrasonography in evaluation and treatment of patients with apical and anterior POP.

Consolidation durvalumab is standard of care in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression following chemoradiotherapy (the 'PACIFIC regimen'). However, many patients with poor performance status, older age or comorbidities may be ineligible for chemotherapy due to expected high toxicity. These patients typically receive radiotherapy alone, with poor survival outcomes. Based on the PACIFIC trial data, and the strong biological rationale for combining radiotherapy with anti-programmed cell death ligand-1 therapy, durvalumab following radiotherapy could provide additional survival benefit versus radiotherapy alone. Here, we describe the DUART trial, a Phase II, open-label, single-arm study assessing the safety and tolerability of durvalumab following radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy (ClinicalTrials.gov Identifier: NCT04249362).Lay abstract The current standard treatment for patients with stage III non-small-cell lung cancer whose cancer cannot be removed by surgery is chemotherapy plus radiotherapy; if their disease gets no worse after this, patients also receive durvalumab – altogether this is known as the ‘PACIFIC regimen’. However, some patients who are older or who have existing health conditions cannot tolerate chemotherapy, so instead of the PACIFIC regimen they receive radiotherapy only. The DUART study described here is an ongoing, Phase II clinical trial looking at the safety and tolerability of durvalumab after radiotherapy in patients with stage III non-small-cell lung cancer who are unsuitable for chemotherapy and whose cancer cannot be removed by surgery. Clinical Trial Registration: NCT04249362.

Objective: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. Background: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. Methods: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18–65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70mg, administered subcutaneously every 4weeks. Treatment duration was planned to last from 6 to 12months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9–12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). Results: In total, 372 migraine patients were treated with at least one dose of erenumab 70mg. At weeks 9–12, erenumab decreased MMDs by 4.5±4.1days (mean±SD) in patients with HFEM and by 9.3±9.1 (mean±SD) days in those with CM compared to baseline. At weeks 9–12 VAS score was reduced by 1.9±1.9 (mean±SD), HIT score by 10.7±8.8 (mean±SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0–14.0) to 5.0 (IQR 3.0–7.0) in HFEM. In CM patients, VAS was reduced by 1.7±2.0 (mean±SD), HIT by 9.7±10.4 (mean±SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0–30.0) to 8.0 (IQR 5.0–15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24–7.40; p=0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02–1.11; p=0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14–3.52; p=0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20–0.93; p=0.003). Conclusions: Erenumab 70mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

Previous studies reported a positive effect of anti-CGRP monoclonal antibodies (mAbs) in migraine prevention, either in over (O65) and under (U65) 65-year-aged patients. The aim of our study was to evaluate and compare real-life efficacy and safety of mAbs between young and elder migraine patients. Fifteen O65 and fifteen U65 patients, treated with monthly mAbs for 6 months, were enrolled and matched for sex, monthly headache days (MHD), and monthly migraine days (MMD) at baseline. Between-group differences in MHD and MMD, number of pills and days of acute medication intake, HIT-6, MIDAS, Numeric Rating Scale (NRS), and Allodynia Symptom Checklist (ASC-12) were assessed after 3 (M3) and 6 (M6) months of treatment. Adverse events (AEs) were also investigated. In each group, thirteen patients (87%) were women and nine (60%) had chronic migraine. Baseline mean MHD and MMD of both groups were 20 (SD 9.6). Mean age was 70 (65-76) and 45 (19-55) in the O65 and U65 group, respectively. Before starting mAbs, patients have tried an average of 4 preventives in both groups. After 3 and 6 months of treatment, both groups had a reduction of all clinical features under examination, without statistically significant differences between groups. A similar proportion of patients in each group complained of AEs (M3 and M6, p = 1.0). Our real-life data showed that treatment with mAbs is as effective and safe in O65 as U65 migraine patients. Further studies are needed to confirm these findings.

International audience; Background and AimsThe identification of Crohn's disease (CD)-associated adherent and invasive Escherichia coli (AIEC) is time-consuming and requires ileal biopsies. We aimed to identify a faster and less invasive methods to detect ileal colonization by AIEC in CD patients.MethodsCD patients requiring ileo-colonoscopy were consecutively enrolled in this prospective multicenter study. Samples from saliva, serum, stools, and ileal biopsies of CD patients were collected.ResultsAmong 102 CD patients, the prevalence of AIEC on ileal biopsies was 24.5%. The abundance and global invasive ability of ileal-associated total E. coli were respectively ten-fold (p = 0.0065) and two-fold (p = 0.0007) higher in AIEC-positive (vs. AIEC-negative), while abundance of total E. coli in the feces was not correlated with AIEC status in the ileum. The best threshold of ileal total E. coli was 60 cfu/biopsy to detect AIEC-positive patients, with high negative predictive value (NPV) (94.1%[80.3–99.3]), while the global invasive ability (>9000 internalized bacteria) was able to detect the presence of AIEC with high positive predictive value (80.0% [55.2–100.0]). Overall, 78.1% of the AIEC + patients were colonized by two or less different AIEC strains. The level of serum anti-total E. coli antibodies (AEcAb) was higher in AIEC-positive patients (p = 0.038) with a very high negative predictive value (96.6% [89.9–100.0]) (p = 0.038) for a cut-off value > 1.9 × 10−3.ConclusionsMore than two thirds of AIEC-positive CD patients were colonized by two or less AIEC strains. While stools samples are not accurate to screen AIEC status, the AEcAb level appears to be an attractive, rapid and easier biomarker to identify patients with Crohn's disease harboring AIEC.

The advent of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival in patients with peritoneal surface malignancies. Not surprisingly, there is now a growing interest on the possible means to preserve fertility to ensure future childbearing. In this study, we report on five women with peritoneal surface malignancies who performed ovarian hyper-stimulation and oocytes cryostorage prior to undergo CRS and HIPEC. The presence of the disease complicated follicular growth monitoring but the oocytes retrievals could be always performed and were uneventful. At last follow-up, all women were alive and disease-free. None has yet returned to thaw her oocytes. Overall, these cases suggest that oocytes cryopreservation before CRS and HIPEC should be considered.

OBJECTIVE: To investigate the level and determinants of nonreceipt of contraception among women admitted to facilities with abortion-related complications in East and Southern Africa. METHODS: Cross-sectional data from Kenya, Malawi, Mozambique, and Uganda collected as part of the World Health Organization (WHO) Multi-Country Survey on Abortion-related morbidity. Medical record review and the audio computer-assisted self-interviewing system were used to collect information on women's demographic and clinical characteristics and their experience of care. The percentage of women who did not receive a contraceptive was estimated and the methods of choice for different types of contraceptives were identified. Potential determinants of nonreceipt of contraception were grouped into three categories: sociodemographic, clinical, and service-related characteristics. Generalized estimating equations were used to identify the determinants of nonreceipt of a contraceptive following a hierarchical approach. RESULTS: A total of 1190 women with abortion-related complications were included in the analysis, of which 33.9% (n = 403) did not receive a contraceptive. We found evidence that urban location of facility, no previous pregnancy, and not receiving contraceptive counselling were risk factors for nonreceipt of a contraceptive. Women from nonurban areas were less likely not to receive a contraceptive than those in urban areas (AOR 0.52; 95% CI, 0.30-0.91). Compared with women who had a previous pregnancy, women who had no previous pregnancy were 60% more likely to not receive a contraceptive (95% CI, 1.14-2.24). Women who did not receive contraceptive counselling were over four times more likely to not receive a contraceptive (AOR 4.01; 95% CI, 2.88-5.59). CONCLUSION: Many women leave postabortion care having not received contraceptive counselling and without a contraceptive method. There is a clear need to ensure all women receive high-quality contraceptive information and counselling at the facility to increase contraceptive acceptance and informed decision-making.

Background Periorbital fractional CO2 laser resurfacing has been employed for facial rejuvenation purposes. However, to the best of our knowledge, no study has objectively assessed periorbital neoformation and remodeling of local cutaneous collagen, in a split-face model, from skin samples obtained during upper blepharoplasty. Objectives The authors sought to objectively evaluate neoformation and remodeling of local cutaneous collagen after periorbital skin fractional CO2 laser resurfacing. Methods Sixteen female patients presenting with dermatochalasis and periorbital rhytids were evaluated in a prospective and comparative study. All patients underwent unilateral periorbital fractional CO2 laser resurfacing 30 days before upper blepharoplasty. Quantification of types I and III collagen from laser-treated and untreated eyelid skin samples obtained during upper blepharoplasty was assessed with histochemical analysis (Picrosirius Red staining). Laser resurfacing treatment was applied to the untreated side immediately after the upper blepharoplasty. Two blinded, independent physicians evaluated clinical improvement in pretreatment and 1- and 6-month posttreatment digital images. Results Histochemical analysis showed significantly higher intensity in collagen types I (treated: 158.7 ± 5.3, untreated: 139.2 ± 5.0; P Conclusions Periorbital fractional CO2 laser resurfacing was an effective method to improve palpebral skin, with histochemical evidence of increase in collagen types I and III. Level of Evidence: 4

Objective To assess the proportion of female childhood and adolescent tumor survivors who could benefit from oocyte cryopreservation. Design Case series of female childhood and adolescent tumor survivors referred for fertility counseling. Setting A referral cancer center and an infertility unit of an academic hospital. Patient(s) Young female childhood and adolescent tumor survivors who received gonadotoxic treatments. Intervention(s) Patients were prescribed tests of ovarian reserve and a personalized counseling was given. Oocyte cryopreservation was considered in subjects aged ≥18 years who were diagnosed with diminished ovarian reserve (DOR) (antimullerian hormone level Main Outcome Measure(s) Rate of women with DOR who stored their oocytes. Result(s) Ninety out of 126 evaluated women completed the assessments. We documented preserved ovarian reserve, DOR, and premature ovarian insufficiency in 36 (40%), 35 (39%), and 19 (21%) cases, respectively. Overall, 13 subjects with DOR were eligible for oocyte cryostorage, of whom 9 (69%) underwent the procedure. Considering the whole cohort of evaluated young women (n = 90), the rate of those who had egg freezing was 10%. Finally, nine women started seeking pregnancy after the counseling (six with DOR), and seven of them became pregnant. When the data were analyzed separately according to most gonadotoxic treatments, considerable differences emerged but the evidence did not support the idea that counseling should be restricted to particular subgroups of women. Conclusion(s) Ovarian reserve impairment is common in female childhood and adolescent tumor survivors. Postcancer oocyte cryopreservation may be part of the armamentarium of fertility preservation options.