The role of adjuvant chemotherapy in patients with H3K27 altered diffuse midline gliomas: a multicentric retrospective study.

PURPOSE: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. METHODS: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. RESULTS: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1-68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05-0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03-0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1-0.65, p = 0.004). CONCLUSION: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed.

Comorbidity in myasthenia gravis: multicentric, hospital-based, and controlled study of 178 Italian patients.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder with fluctuating weakness that causes significant disability and morbidity. Comorbidities may influence the course of MG, particularly in specific subgroups. The aim of this study is to investigate the frequency of comorbidities in MG patients compared to healthy controls (HC) and to evaluate their distribution according to age at disease onset, sex, and disease severity. METHODS: MG patients attending the University Hospital "Paolo Giaccone" in Palermo and "SS Annunziata" Hospital in Chieti were enrolled; HC were enrolled from the general population. Non-parametric statistics and logistic regression were used to assess the association of specific comorbidities according to age at disease onset, sex, disease subtypes, and severity of the disease. RESULTS: A total of 356 subjects were included in the study: 178 MG patients (46% F; median age 60 years [51-71]) and 178 sex- and age-matched HC (46% F, median age 59 years [50-66]). Overall, 86% of MG patients and 76% of HC suffered from comorbidities, and MG patients had a higher number of comorbidities compared to HC. Patients with late-onset suffered from more comorbidities than those with early-onset MG. Hypertension was more common in male patients with MG, while thymic hyperplasia, osteoporosis, and autoimmune diseases were more common in females. Respiratory disorders and thymoma were more common in patients with more severe disease (p < 0.05 for all comparisons). CONCLUSION: MG patients, particularly those with late onset, showed a higher prevalence of comorbidities than HC. Assessment of comorbidities in MG is an essential issue to identify the appropriate treatment and achieve the best management.

Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy.

BACKGROUND: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). METHODS: People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. RESULTS: 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73-0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51-0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). CONCLUSIONS: PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.

Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD).

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Expanding the clinical and genetic spectrum of pathogenic variants in STIM1.

INTRODUCTION/AIMS: Stromal interaction molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1. METHODS: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. RESULTS: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients. DISCUSSION: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.

Rituximab in AChR subtype of myasthenia gravis: systematic review.

Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction characterised by an autoantibody against acetylcholine receptor (AChR-Ab), autoantibody against muscle-specific kinase (MuSK-Ab), lipoprotein-related protein 4 or agrin in the postsynaptic membrane at the neuromuscular junction. Many patients are resistant to conventional treatment and effective therapies are needed. Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen on B cells which has been successfully employed in anti-MuSK-Ab+MG, but the efficacy in anti-AChR-Ab+MG is still debated. The purpose of this systematic review was to describe the best evidence for RTX in the acetylcholine receptor subtype. The authors undertook a literature search during the period of 1999-2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analys methodology, employing (myasthenia)+(gravis)+(RTX) as search terms. The analysis was confined to studies that include at least five patients with confirmed anti-AChR-Ab+MG. Thirteen studies have been selected, showing a good safety. The data obtained were heterogeneous in terms of posology, administration scheme and patients' evaluation, ranging from a minimum of two to a maximum of three cycles. RTX led to a sustained clinical improvement with prolonged time to relapse, in parallel to a reduction or discontinuation of other immunosuppressive therapies. Treatment with RTX appears to work in some but not all patients with anti-AChR-Ab+MG, but randomised controlled trials are needed. Future studies should take into account the subtype of MG and employ reliable measures of outcome and severity focusing on how to identify patients who may benefit from the treatment. Trial registration number: NCT02110706.

Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (≤8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.

Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (≤ 8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1-3 repeats or 4-8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4-8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4-8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family's genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.

Brain metastases and next-generation anticancer therapies: a survival guide for clinicians.

Historically, patients with brain metastases (BMs) have been characterized by few systemic treatment options and poor prognosis. The recent introduction of next-generation anticancer therapies such as molecular targeted agents and immunotherapy have revolutionized the clinical decision-making process of this sub-population, posing new challenges to physicians. In this review, current evidence for the use of checkpoint inhibitors and targeted therapies in patients with BMs are discussed, with a focus on lung cancer, breast cancer, melanoma and renal cell carcinoma, providing suggestions and potential workflows for daily clinical practice. Several other on-going and future challenges, such as clinical trials design, ways to improve CNS penetration of novel drugs and unique molecular characteristics of BMs, are also discussed. The aim is producing an updated and easy-to-read guide for physicians, to improve decision-making in clinical practice.

T Cell Features in Glioblastoma May Guide Therapeutic Strategies to Overcome Microenvironment Immunosuppression.

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients' prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting. Probably this has to do with the unique immune environment of the central nervous system, which harbors several immunosuppressive/pro-tumorigenic factors, both soluble (e.g., TGF-ß, IL-10, STAT3, prostaglandin E2, and VEGF) and cellular (e.g., Tregs, M2 phenotype TAMs, and MDSC). Here we review the immune composition of the GBMs microenvironment, specifically focusing on the phenotype and function of the T cell compartment. Moreover, we give hints on the therapeutic strategies, such as immune checkpoint blockade, vaccinations, and adoptive cell therapy, that, interacting with tumor-infiltrating lymphocytes, might both target in different ways the tumor microenvironment and potentiate the activity of standard therapies. The path to be followed in advancing clinical research on immunotherapy for GBM treatment relies on a twofold strategy: testing combinatorial treatments, aiming to restore active immune anti-tumor responses, tackling immunosuppression, and additionally, designing more phase 0 and window opportunity trials with solid translational analyses to gain deeper insight into the on-treatment shaping of the GBM microenvironment.

Refining patient selection for next-generation immunotherapeutic early-phase clinical trials with a novel and externally validated prognostic nomogram.

Introduction: Identifying which patient may benefit from immunotherapeutic early-phase clinical trials is an unmet need in drug development. Among several proposed prognostic scores, none has been validated in patients receiving immunomodulating agents (IMAs)-based combinations. Patients and methods: We retrospectively collected data of 208 patients enrolled in early-phase clinical trials investigating IMAs at our Institution, correlating clinical and blood-based variables with overall survival (OS). A retrospective cohort of 50 patients treated with IMAs at Imperial College (Hammersmith Hospital, London, UK) was used for validation. Results: A total of 173 subjects were selected for analyses. Most frequent cancers included non-small cell lung cancer (26%), hepatocellular carcinoma (21.5%) and glioblastoma (13%). Multivariate analysis (MVA) revealed 3 factors to be independently associated with OS: line of treatment (second and third vs subsequent, HR 0.61, 95% CI 0.40-0.93, p 0.02), serum albumin as continuous variable (HR 0.57, 95% CI 0.36-0.91, p 0.02) and number of metastatic sites (<3 vs ≥3, HR 0.68, 95% CI 0.48-0.98, p 0.04). After splitting albumin value at the median (3.84 g/dL), a score system was capable of stratifying patients in 3 groups with significantly different OS (p<0.0001). Relationship with OS reproduced in the external cohort (p=0.008). Then, from these factors we built a nomogram. Conclusions: Prior treatment, serum albumin and number of metastatic sites are readily available prognostic traits in patients with advanced malignancies participating into immunotherapy early-phase trials. Combination of these factors can optimize patient selection at study enrollment, maximizing therapeutic intent.

Effectiveness and Safety of Mycophenolate Mophetil in Myasthenia Gravis: A Real-Life Multicenter Experience.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating muscle weakness due to autoantibodies targeting neuromuscular junction proteins. Mycophenolate mofetil (MMF), an immunosuppressive therapy, has shown potential for managing MG with fewer side effects compared to other treatments. This study aims to evaluate the effectiveness and safety of MMF in MG patients in a real-life multicenter setting. METHODS: A retrospective cohort study was conducted on generalized MG patients, refractory to azathioprine (AZA) and treated with MMF alone or with steroids, at three Italian centers from January 2011 to February 2024. Patients were assessed using the Myasthenia Gravis Foundation of America (MGFA) classification, MG composite score (MGCS), and MG activity of daily living (MGADL) scores at baseline, 6, 12, 18, and 24 months. Statistical analyses included the Spearman correlation, the Friedman test, and ANOVA. RESULTS: Thirty-two patients were enrolled (13 males, mean age 66.5 ± 11.5 years). Significant improvements in MGADL and MGCS scores were observed at 6 and 12 months (p < 0.001), with continued improvement over 24 months. Side effects were reported in 12% of patients. MMF showed a faster onset of symptom control compared to azathioprine, with a significant improvement noted within 6 months. CONCLUSIONS: A recent study found that MMF and AZA were equally effective in improving patients' quality of life, but because AZA had more serious adverse events than MMF, lower doses of AZA were therefore recommended to reduce the adverse events while maintaining efficacy. Conversely, results showed that MMF is effective and well-tolerated in the long-term management of MG, providing faster symptom control and a favorable safety profile. Future prospective studies with larger cohorts are needed to confirm these findings and explore sex differences in response to MMF treatment.

Immune-checkpoint inhibitors in anal squamous cell carcinoma: a systematic review and meta-analysis.

INTRODUCTION: Squamous cell carcinoma of the anus (SCCA) is a rare tumor. While most patients with locally advanced disease are cured with chemo-radiotherapy, about a quarter eventually experience metastatic recurrence. Standard treatment for advanced disease is chemotherapy, but recently evidence on the activity of immunotherapy has been reported. We performed a systematic review and meta-analysis of prospective trials testing immune-checkpoint inhibitors (ICIs) in patients with SCCA. OBJECTIVE: We aimed to evaluate the overall response rate (ORR) and the disease control rate (DCR) of ICIs in patients with advanced SCCA. METHODS: We systematically searched PubMed, Embase, and Scopus, through December 31, 2022, for prospective trials assessing ICIs in patients with advanced SCCA. The primary and secondary endpoints were respectively ORR and DCR. RESULTS: Six prospective trials were included in the analysis, one of which was randomized. Overall, seven treatment arms and 347 patients have been analyzed. Five treatment arms tested ICIs as monotherapy and two arms examined ICIs in combination with cetuximab and bevacizumab, respectively. The pooled ORR was 13% (95%CI, 10%-17%), with a DCR of 57% (95%CI, 40%-74%). Results did not change in a sensitivity analysis, which excluded the two treatment arms testing the combination of ICIs with other drugs. CONCLUSIONS: The efficacy of ICIs in SCCAs is low. Combination strategies with targeted drugs or chemotherapy might represent a better therapeutic strategy for these patients. Further studies are awaited to identify resistance mechanisms to ICIs and optimize their efficacy.

Improved outcomes in women with BRAF-mutant melanoma treated with BRAF/MEK-targeted therapy across randomized clinical trials. A systematic review and meta-analysis.

Available evidence suggests that in patients with advanced BRAF V600-mutant melanoma treated with the combination of BRAF and MEK inhibitors, gender could be associated with survival outcome. We performed a systematic review and meta-analysis of all randomized clinical trials (RCTs) testing the combination of BRAF and MEK inhibitors, to assess the interaction between treatment effect and patients' gender. We searched PubMed, MEDLINE, Embase, and Scopus, for phase II and III RCTs up to January 30, 2022. We included all RCTs that enrolled patients with BRAF V600-mutant advanced cutaneous melanoma and assessed combinations of BRAF and MEK inhibitors versus BRAF inhibitor monotherapy. Our aim was to assess differences if any in treatment efficacy between men and women, measured in terms of the differences in progression-free survival (PFS) and overall survival (OS) log-hazard ratios (log-HRs). We calculated the pooled PFS- and OS-HRs with 95% confidence intervals (CIs) in men and women using a random-effects model and assessed the heterogeneity between the estimates using an interaction test. Five RCTs that enrolled a total of 2,113 patients were included in the analysis. In women, the combination of BRAF and MEK inhibitors halved the risk of progression or death as compared with BRAF inhibitor monotherapy with a pooled PFS-HR of 0.50 (95%CI 0.41-0.61). In men, the benefit obtained with BRAF and MEK inhibitors was smaller with a pooled PFS-HR of 0.63 (95%CI 0.54-0.74), P-heterogeneity = .05. A similar trend was observed for OS where the pooled OS-HR was 0.62 (95%CI 0.48-0.80) in women and only 0.78, (95%CI 0.67-0.92) in men, P-heterogeneity = 0.11. These results support meaningful gender-based heterogeneity of response to combination of BRAF and MEK inhibitors targeted therapy in patients with advanced BRAF-mutant melanoma, that should be considered in future research to improve treatment effectiveness.

Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations.

Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest "driver" genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply "precision oncology" in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.

Adherence and Reactogenicity to Vaccines against SARS-COV-2 in 285 Patients with Neuropathy: A Multicentric Study.

Background: The safety of the new vaccines against SARS-CoV-2 have already been shown, although data on patients with polyneuropathy are still lacking. The aim of this study is to evaluate the adherence to SARS-CoV-2 vaccination, as well as the reactogenicity to those vaccines in patients affected by neuropathy. Methods: A multicentric and web-based cross-sectional survey was conducted among patients affected by neuropathy from part of South Italy. Results: Out of 285 responders, n = 268 were included in the final analysis and n = 258 of them (96.3%) were fully vaccinated. Adherence to vaccination was higher in patients with hereditary neuropathies compared to others, while it was lower in patients with anti-MAG neuropathy (all p < 0.05). The overall prevalence of adverse events (AEs) was 61.2% and its occurrence was not associated with neuropathy type. Being female and of younger age were factors associated with higher risk of AEs, while having an inflammatory neuropathy and steroids assumption were associated with a lower risk (all p < 0.05). Younger age, having had an AE, and COVID-19 before vaccination were factors associated with symptoms worsening after vaccination (all p < 0.05). (4) Conclusions: Patients with neuropathy showed a high level of adherence to COVID-19 vaccination. Safety of vaccines in patients with neuropathies was comparable to the general population and it was more favorable in those with inflammatory neuropathy.

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network.

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

Median-to-Ulnar Nerve Communication in Carpal Tunnel Syndrome: An Electrophysiological Study.

The median-to-ulnar communicating branch (MUC) is an asymptomatic variant of the upper limb innervation that can lead to interpretation errors in routine nerve conduction studies. The diagnosis of carpal tunnel syndrome (CTS) or ulnar nerve lesions can be complicated by the presence of MUC. In this study, we describe electrophysiological features of MUC in CTS patients presenting to our clinic. We enrolled MUB cases from consecutive CTS patients referred to our laboratory between the years 2014 and 2019. MUC was present in 53 limbs (36 patients) from the studied population. MUC was bilateral in 53% of patients. MUC type II was the most common subtype (74%), followed by types III and I; more coexisting MUC types were found in the majority of tested limbs. A positive correlation was demonstrated between the severity of CTS and the presence of positive onset, faster CV, or a double component of the compound muscle action potentials. We emphasize the importance of suspecting the presence of MUC in CTS in the presence of a positive onset or a double component in routine motor conduction studies.

ATTRv in Lazio-Italy: A High-Prevalence Region in a Non-Endemic Country.

Hereditary transthyretin amyloidosis (ATTRv, v for variant) prevalence in Italy, a non-endemic region, has been established by ATTRv amyloidosis Italian Registry. However, values of prevalence were extremely heterogeneous, considering different regions. To properly establish the prevalence of the disease in the Lazio region, a survey was sent to university regional hospitals and to main regional hospitals, in order to collect all affected patients regularly followed. We identified 100 ATTRv patients and, considering a Lazio population of 5.8/million, we estimated a ATTRv prevalence of 17.2/million. The ATTRv amyloidosis Italian Registry reported a prevalence of 8.0/million in Lazio, while our survey showed a value of double this. Our survey documented a high-prevalence for a non-endemic country. The increased awareness of the disease among general practitioners and medical specialists is a fundamental step to reduce the diagnostic delay and start an effective treatment of this disease.