Regional hippocampal atrophy reflects memory impairment in patients with early relapsing remitting multiple sclerosis.

BACKGROUND: Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients. METHODS: From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes. RESULTS: Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23-0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group. CONCLUSION: Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients.

Functional gradients reveal cortical hierarchy changes in multiple sclerosis.

Functional gradient (FG) analysis represents an increasingly popular methodological perspective for investigating brain hierarchical organization but whether and how network hierarchy changes concomitant with functional connectivity alterations in multiple sclerosis (MS) has remained elusive. Here, we analyzed FG components to uncover possible alterations in cortical hierarchy using resting-state functional MRI (rs-fMRI) data acquired in 122 MS patients and 97 healthy control (HC) subjects. Cortical hierarchy was assessed by deriving regional FG scores from rs-fMRI connectivity matrices using a functional parcellation of the cerebral cortex. The FG analysis identified a primary (visual-to-sensorimotor) and a secondary (sensory-to-transmodal) component. Results showed a significant alteration in cortical hierarchy as indexed by regional changes in FG scores in MS patients within the sensorimotor network and a compression (i.e., a reduced standard deviation across all cortical parcels) of the sensory-transmodal gradient axis, suggesting disrupted segregation between sensory and cognitive processing. Moreover, FG scores within limbic and default mode networks were significantly correlated ( ρ = 0.30 $$ \rho =0.30 $$ , p < .005 after Bonferroni correction for both) with the symbol digit modality test (SDMT) score, a measure of information processing speed commonly used in MS neuropsychological assessments. Finally, leveraging supervised machine learning, we tested the predictive value of network-level FG features, highlighting the prominent role of the FG scores within the default mode network in the accurate prediction of SDMT scores in MS patients (average mean absolute error of 1.22 ± 0.07 points on a hold-out set of 24 patients). Our work provides a comprehensive evaluation of FG alterations in MS, shedding light on the hierarchical organization of the MS brain and suggesting that FG connectivity analysis can be regarded as a valuable approach in rs-fMRI studies across different MS populations.

Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.

Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.

Vocabulary knowledge as a reliable proxy of cognitive reserve in multiple sclerosis: a validation study.

INTRODUCTION: The present study aimed to explore the suitability of the vocabulary knowledge (VOC) test as an accurate and reliable proxy of cognitive reserve (CR) by evaluating its psychometric properties and discrimination accuracy compared with other CR measures in multiple sclerosis (MS). METHODS: Sixty-eight consecutive people with multiple sclerosis (pwMS), followed at our MS outpatient clinic, completed a clinical evaluation and neuropsychological assessment including: VOC, Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Cognitive Reserve Index Questionnaire (CRIq), Beck Depression Inventory-II, and State-Trait Anxiety Inventory. Reliability, convergent and divergent validity, and discrimination accuracy of the VOC were assessed using educational level as reference standard. The possible effects of sociodemographic and clinical factors on VOC and their role in predicting global cognitive status were also explored. RESULTS: VOC demonstrated good internal consistency (Cronbach's α = 0.894) and adequate construct validity. It showed an acceptable level of discrimination between pwMS with high and low CR, comparable to the CRIq score. Education strongly affected VOC scores, which in turn were independent of MS features. VOC emerged as an independent predictor of global cognitive status together with MS-related disability. CONCLUSION: We demonstrated the validity of VOC as a reliable CR measure in pwMS. Thus, CR may also be estimated using fixed objective measures, independent of brain pathology and clinical features. Early CR estimation may help clinicians identify pwMS at a higher risk of cognitive decline and plan strict neuropsychological monitoring and cognitive interventions.

The brief repeatable battery of neuropsychological tests (BRB-N) version a: update of Italian normative data from the Italian Neuroimaging Network Initiative (INNI).

BACKGROUND: Cognitive impairment is a common clinical manifestation in people with multiple sclerosis (PwMS) and significantly impacts patients' quality life. Cognitive assessment is crucial for treatment decisions and understanding disease progression. Several neuropsychological batteries are used in MS, including the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Minimal Assessment of Cognitive Function in MS (MACFIMS), and Brief International Cognitive Assessment for MS (BICAMS). However, normative data for BRB-N version A in Italy are outdated. OBJECTIVES: To revise and update normative data for the BRB-N version A in the Italian population. METHODS: From the Italian Neuroimaging Network Initiative (INNI) database, we retrospectively selected 342 healthy subjects (172 males and 170 females) evaluated at four Italian INNI-affiliated sites (Milan, Siena, Rome, Naples). The subjects underwent neuropsychological assessment using the BRB-N version A. Regression-based method relying on scaled scores was used to calculate demographic correction procedures. RESULTS: No significant differences were found in age, education, and sex distribution among the four sites (p ≥ 0.055). Regression analysis provided normative data to calculate demographically adjusted z-scores for each BRB-N version A test. DISCUSSION: This study provides updated normative data for the BRB-N version A in the Italian population. The use of a regression-based method and scaled scores ensures consistency with other neuropsychological batteries commonly used in Italy, namely MACFIMS and BICAMS. The availability of updated normative data increases reliability of neuropsychological assessment of cognitive function in Italian PwMS and other clinical populations using BRB-N version A, providing valuable insights for both clinical and research applications.

Quality of care provided by Multiple Sclerosis Centers during Covid-19 pandemic: Results of an Italian multicenter patient-centered survey.

BACKGROUND: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed. METHODS: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance. RESULTS: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic. CONCLUSIONS: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC.

Efficacy and safety of tixagevimab-cilgavimab (Evusheld®) in people with Multiple Sclerosis on Ocrelizumab: preliminary evidence.

BACKGROUND: Evusheld (EVS) was authorized by FDA and EMA as pre-exposure prophylaxis (PrEP) in people at high risk of severe Covid-19 outcomes, including people with Multiple Sclerosis (pwMS) on B-cell depleting (BCD) therapies-such as Ocrelizumab (OCR). In this population, no data on possible adverse drug reactions (ADRs) to EVS, B-lymphocytes (CD20 +) counts pre- and post-EVS injection, and comparison of percentage increase of IgG antibodies directed against SARS-CoV-2 trimeric spike protein (anti-TSP IgG) post-EVS and Covid-19 vaccine was available. The aim of this study was to better characterize the efficacy and safety profile of EVS in pwMS on BCD agents. METHODS: 17 pwMS on OCR agreed to receive EVS as PrEP for Covid-19. Sera samples were collected before the first dose of Covid-19 vaccine (T0), 4 weeks after the second dose (T1), 4 weeks after third dose (T2), immediately before (T3) and 4 weeks after (T4) EVS. RESULTS: Covid-19 vaccine ADRs were mild-to-moderate, whereas no ADRs were reported after EVS injection. A significant increase of anti-TSP IgG was found only at T0-T1 (Z = -3.059, p = .002) and T3-T4 (Z = -3.621, p < .001) time-points. The median percentage increase between T3-T4 was significantly higher with respect to the T0-T1(Z = -3.296, p = .001) and T1-T2 (Z = -3.059, p = .002) time-points. CONCLUSIONS: These results further support EVS safety and efficacy in boosting anti-TSP IgG titers in pwMS on OCR, with a statistically greater increase than that observed after completion of a full Covid-19 vaccine cycle, plus a booster dose.

Validation of an iPad version of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS).

BACKGROUND: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is the most widely used screening tool for cognitive impairment in Multiple Sclerosis (MS). However, the administration and scoring procedures of the paper version are time consuming and prone to errors. Aim of our study was to develop a tablet version of BICAMS (iBICAMS), and to assess its reliability compared to the paper version. METHODS: We administered both BICAMS and iBICAMS to 139 MS patients in two different sessions. We compared scores on both versions using a paired t-test. We used a repeated measures ANOVA to test the impact of rater, order of administration and test-retest time on test-retest performances. We used the Intraclass Correlation Coefficient (ICC) to assess the reliability between BICAMS and iBICAMS. RESULTS: All three sub-tests of the BICAMS (SDMT, CVLT-II and BVMT-R) were different between the paper and the tablet versions. Order of administration influenced test-retest performances at the SDMT (p<0.001), CVLT- II (p<0.001) and BVMT-R (p<0.001). Intraclass coefficient correlation (ICC) revealed a high level of agreement between the paper BICAMS and the iPad version for all three tests: SDMT (0.92), CVLT-II (0.83) and BVMT-R (0.82). CONCLUSIONS: We found a high reliability between BICAMS and iBICAMS. Considering the inherent advantages of automated scoring, digital storage of data, standardized timing, the iBICAMS could become a standard in clinical practice.

Prediction of the information processing speed performance in multiple sclerosis using a machine learning approach in a large multicenter magnetic resonance imaging data set.

Many patients with multiple sclerosis (MS) experience information processing speed (IPS) deficits, and the Symbol Digit Modalities Test (SDMT) has been recommended as a valid screening test. Magnetic resonance imaging (MRI) has markedly improved the understanding of the mechanisms associated with cognitive deficits in MS. However, which structural MRI markers are the most closely related to cognitive performance is still unclear. We used the multicenter 3T-MRI data set of the Italian Neuroimaging Network Initiative to extract multimodal data (i.e., demographic, clinical, neuropsychological, and structural MRIs) of 540 MS patients. We aimed to assess, through machine learning techniques, the contribution of brain MRI structural volumes in the prediction of IPS deficits when combined with demographic and clinical features. We trained and tested the eXtreme Gradient Boosting (XGBoost) model following a rigorous validation scheme to obtain reliable generalization performance. We carried out a classification and a regression task based on SDMT scores feeding each model with different combinations of features. For the classification task, the model trained with thalamus, cortical gray matter, hippocampus, and lesions volumes achieved an area under the receiver operating characteristic curve of 0.74. For the regression task, the model trained with cortical gray matter and thalamus volumes, EDSS, nucleus accumbens, lesions, and putamen volumes, and age reached a mean absolute error of 0.95. In conclusion, our results confirmed that damage to cortical gray matter and relevant deep and archaic gray matter structures, such as the thalamus and hippocampus, is among the most relevant predictors of cognitive performance in MS.

Resting-state functional MRI in multicenter studies on multiple sclerosis: a report on raw data quality and functional connectivity features from the Italian Neuroimaging Network Initiative.

The Italian Neuroimaging Network Initiative (INNI) is an expanding repository of brain MRI data from multiple sclerosis (MS) patients recruited at four Italian MRI research sites. We describe the raw data quality of resting-state functional MRI (RS-fMRI) time-series in INNI and the inter-site variability in functional connectivity (FC) features after unified automated data preprocessing. MRI datasets from 489 MS patients and 246 healthy control (HC) subjects were retrieved from the INNI database. Raw data quality metrics included temporal signal-to-noise ratio (tSNR), spatial smoothness (FWHM), framewise displacement (FD), and differential variation in signals (DVARS). Automated preprocessing integrated white-matter lesion segmentation (SAMSEG) into a standard fMRI pipeline (fMRIPrep). FC features were calculated on pre-processed data and harmonized between sites (Combat) prior to assessing general MS-related alterations. Across centers (both groups), median tSNR and FWHM ranged from 47 to 84 and from 2.0 to 2.5, and median FD and DVARS ranged from 0.08 to 0.24 and from 1.06 to 1.22. After preprocessing, only global FC-related features were significantly correlated with FD or DVARS. Across large-scale networks, age/sex/FD-adjusted and harmonized FC features exhibited both inter-site and site-specific inter-group effects. Significant general reductions were obtained for somatomotor and limbic networks in MS patients (vs. HC). The implemented procedures provide technical information on raw data quality and outcome of fully automated preprocessing that might serve as reference in future RS-fMRI studies within INNI. The unified pipeline introduced little bias across sites and appears suitable for multisite FC analyses on harmonized network estimates.

AQP4-MOG Double-Positive Neuromyelitis Optica Spectrum Disorder: Case Report with Central and Peripheral Nervous System Involvement and Review of Literature.

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system.

Efficacy and safety of belantamab-mafodotin in triple-refractory multiple myeloma patients: A multicentric real-life experience.

Belantamab-mafodotin is an innovative and selective treatment for multi-refractory/relapsed multiple myeloma (MM) patients; however, available real-life experiences on efficacy and safety are limited. In this real-world multicentric retrospective study, we enrolled 28 MM patients treated in four Hematology units of Campania region, Italy, who received a median of six treatment lines prior to belantamab-mafodotin. The overall response rate (ORR) was 40% (complete remission, CR, 11%; very good partial remission, VGPR, 11%; and partial remission, PR, 18%), with a median progression-free survival (PFS) and overall survival (OS) of 3 and 8 months, respectively. One of the most frequent drug-related adverse events was keratopathy observed in nine (32%) patients, leading to therapy discontinuation in only three (11%) of them. Moreover, 22 out of 28 total patients who were treated with at least two administrations achieved an ORR of 50% (CR, 14%; VGPR, 14%; and PR, 22%) with a median PFS and OS of 5 and 11 months, respectively. In conclusion, our multicentric study confirmed efficacy and safety of belantamab-mafodotin in triple-refractory MM patients even in the real-life setting.

Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

Humoral response and safety of the third booster dose of BNT162b2 mRNA COVID-19 vaccine in patients with multiple sclerosis treated with ocrelizumab or fingolimod.

BACKGROUND: The assessment of the safety and the humoral response to a third booster dose of the BNT162b2 mRNA COVID-19 vaccine is relevant in patients with Multiple Sclerosis (pwMS) treated with Ocrelizumab (OCR) or Fingolimod (FNG). METHODS: Serum samples were collected from Healthy controls (HCs) and pwMS treated with OCR or FNG at the following time-points: before the first of two vaccine doses (T0); 8 (T1), 16 (T2), 24 (T3) weeks after the first dose; within 8 weeks before (T0b) and after (T1b) the booster dose. IgG antibodies to SARS-CoV-2 trimeric spike protein (Anti-TSP IgG) were quantified and expressed as binding antibody units (BAU)/mL. RESULTS: 40 HCs, 28 pwMS on OCR and 19 on FNG were included. At T0b 12 (42.9%) pwMS on OCR and 6 (31.6%) on FNG were still positive while, at T1b 16 (57.14%) pwMS on OCR and 16 (84.2%) on FNG, passed the threshold of positivity. The increase of Anti-TSP IgG levels at T1b was higher for: (i) HCs with respect to OCR (p < 0.001) and FNG (p = 0.032) groups; (ii) pwMS on FNG compared with pwMS on OCR (p < 0.001). No socio-demographic, clinical or laboratory variables were able to predict the anti-TSP IgG increase between T0b and T1b. Neither clinical relapses nor severe adverse events were reported in pwMS after each dose of vaccine. CONCLUSIONS: The third booster dose of BNT162b2 mRNA vaccine to OCR- and FNG-treated pwMS revives the humoral response, independently of any clinical variable, and manifests a good safety and tolerability profile.

Impact of post-contrast MRI in the definition of active multiple sclerosis.

BACKGROUND: For multiple sclerosis (MS) phenotypes classification, the presence of "disease activity" can be defined by clinical relapses and/or by magnetic resonance imaging (MRI) through gadolinium-enhancing (Gd+) lesions or new/enlarged T2 lesions. Recent MRI and pathology findings have demonstrated Gd deposition in the brain, suggesting to avoid Gd administration when dispensable. In this scenario, we aimed to evaluate the contribution of post-contrast MRIs to the definition of "active" MS phenotype. METHODS: We retrospectively selected 84 "active" relapsing-remitting MS (RRMS) patients according to Lublin 2013, calculating both the number of Gd+ lesions not detectable as new/unequivocally enlarged on T2 images and the proportion of patients who would be still correctly classified as "active" without Gd administration. RESULTS: 13 out of 164 (7.9%) Gd+ lesions did not correspond to a new/enlarged T2 lesion. Gd administration did not modify the classification of MS as "active" in 83 out of 84 subjects (98.8%). CONCLUSION: The contribution of Gd+ lesions to the correct classification of RRMS patients as "active" is marginal, thus limiting the need of routine Gd administration for this scope. Further studies are warranted to support these conclusions.

Liposomal doxorubicin supercharge-containing front-line treatment in patients with advanced-stage diffuse large B-cell lymphoma or classical Hodgkin lymphoma: Preliminary results of a single-centre phase II study.

We evaluated the impact of liposomal doxorubicin (NPLD) supercharge-containing therapy on interim fluorodeoxyglucose positron emission tomography (interim-FDG-PET) responses in high-risk diffuse large B-cell lymphoma (DLBCL) or classical Hodgkin lymphoma (c-HL). In this phase II study (2016-2021), 81 adult patients with advanced-stage DLBCL (n = 53) and c-HL (n = 28) received front-line treatment with R-COMP-dose-intensified (DI) and MBVD-DI. R-COMP-DI consisted of 70 mg/m2 of NPLD plus standard rituximab, cyclophosphamide, vincristine and prednisone for three cycles (followed by three cycles with NPLD de-escalated at 50 mg/m2 ); MBVD-DI consisted of 35 mg/m2 of NPLD plus standard bleomycin, vinblastine and dacarbazine for two cycles (followed by four cycles with NPLD de-escalated at 25 mg/m2 ). Patients underwent R-COMP-DI and MBVD-DI with a median dose intensity of 91% and 94% respectively. At interim-FDG-PET, 72/81 patients (one failed to undergo interim-FDG-PET due to early death) had a Deauville score of ≤3. At end of treatment, 90% of patients reached complete responses. In all, 20 patients had Grade ≥3 adverse events, and four of them required hospitalisation. At a median 21-months of follow-up, the progression-free survival of the entire population was 77.3% (95% confidence interval 68%-88%). Our data suggest that the NPLD supercharge-driven strategy in high-risk DLBCL/c-HL may be a promising option to test in phase III trials, for improving negative interim-FDG-PET cases incidence.

The psychological impact of Covid-19 pandemic on people with Multiple Sclerosis: A meta-analysis.

BACKGROUND: Covid-19 pandemic caused relevant psychological consequences in the general population. Since people with Multiple Sclerosis (pwMS) are usually at higher risk of psychological distress than age-matched healthy controls (HC), a meta-analytic study was conducted, aimed at evaluating i) differences between pwMS and HC in the psychological variables during the pandemic, ii) differences in the levels of anxiety, depression, stress, sleep disturbances and quality of life before and during the Covid-19 pandemic in pwMS. METHODS: The literature search on three electronic databases yielded 196 studies (113 after the duplicates removal). Seven studies compared psychological variables between pwMS and HC during the pandemic, while seven studies evaluated the pre- vs during the pandemic differences in pwMS. The following outcomes were selected: depression, anxiety, physical QoL, mental QoL, stress, sleep quality/disturbances. Mean weighted effect sizes (ES) were calculated using Hedges'g, via Prometa3 software. RESULTS: During the pandemic, pwMS showed higher levels of depression (g = 0.51, p=.001), anxiety (g = 0.41, p=.032), and stress (g = 0.51, p=.016) compared to HC. The comparison on psychological outcomes before and during the pandemic in pwMS revealed no significant increase during the pandemic on levels of anxiety (g = 0.08, p=.380), depression (g = 0.02, p=.772), mental QoL (g= -0.14, p=.060), physical QoL (g = 0.00, p=.986), whereas sleep quality deteriorated during the pandemic (g = 0.52, p<.001). CONCLUSIONS: In agreement with pre-pandemic literature, pwMS showed higher levels of psychological distress than HC also during the Covid-19 pandemic. Contrariwise, longitudinal studies revealed that, in pwMS, the only psychological-associated variable that worsened significantly was the sleep quality, but this outcome was evaluated only in two studies. Future studies will have to assess/evaluate the long-term psychological consequences of the pandemic on pwMS.

Unmutated IGHV1-69 CLL Clone Displays a Distinct Gene Expression Profile by a Comparative qRT-PCR Assay.

Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease characterized by variable clinical courses among different patients. This notion was supported by the possible coexistence of two or more independent CLL clones within the same patients, identified by the characterization of the B cell receptor immunoglobulin (BcR IG) idiotypic sequence. By using the antigen-binding site of the BcR IG as bait, the identification and isolation of aggressive and drug-resistance leukemic B-cell clones could allow a deeper biological and molecular investigation. Indeed, by the screening of phage display libraries, we previously selected a peptide binder of the idiotypic region of CLL BCR IGs expressing the unmutated rearrangement IGHV1-69 and used it as a probe to perform a peptide-based cell sorting by flow cytometry in peripheral blood samples from patients with CLL. Since the IGHV1-69 clones persisted during the follow-up time in both patients, we explored the possibility of these clones having acquired an evolutive advantage compared to the other coexisting clones in terms of a higher expression of genes involved in the survival and apoptosis escape processes. To this end, we studied the expression patterns of a panel of genes involved in apoptosis regulation and in NF-kB-dependent pro-survival signals by comparative qRT-PCR assays. According to the results, IGHV1-69 clones showed a higher expression of pro-survival and anti-apoptotic genes as compared to the other CLL clones with different immunogenetic characteristics. Moreover, these IGHV1-69 clones did not carry any characteristic genetic lesions, indicating the relevance of our approach in performing a comprehensive molecular characterization of single tumor clones, as well as for designing new personalized therapeutic approaches for the most aggressive and persistent tumor clones.