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Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England’s 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an “FFPEImpact” score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many. Formalin fixation is commonly used in tissue storage; however, this process has traditionally limited downstream whole genome sequencing usage. Here, the authors identify artefactual signatures in FFPE-derived sequencing data and demonstrate the preservation of clinical utility, thus enabling FFPE whole genome sequencing when required.

Breast cancer is the most frequently diagnosed cancer in women. Survival is generally considered favourable, yet some patients remain at risk of early death. We aimed to assess whether comprehensive whole-genome sequencing (WGS) linked to mortality data could add prognostic value to existing clinical measures and identify patients who might respond to targeted therapeutics. In this integrative, retrospective analysis, we analysed 2445 breast cancer tumours (any stage and molecular subtype) collected from 2403 patients recruited through 13 National Health Service Genomic Medicine Centres or hospitals in England affiliated to the 100 000 Genomes Project (100kGP) between 2012 and 2018. We linked 2208 (90%) cases with clinical data; mortality data were obtained for 1188 patients. Following high-depth WGS of tumour and matched normal DNA, we performed comprehensive WGS profiling seeking driver mutations, mutational signatures, and compound algorithmic scores for homologous recombination repair deficiency (HRD), mismatch repair deficiency, and tumour mutational burden. Data from 1803 additional patients with breast cancer from three independent cohorts were used to validate various findings. To evaluate the prognostic value of WGS features, we performed univariable and multivariable Cox regression on data from patients with stage I–III, ER-positive, HER2-negative breast cancer with a cancer-specific mortality endpoint (around 5-year follow-up). Among 2445 tumours in the 100kGP breast cancer cohort, we observed genomic characteristics with immediate personalised medicine potential in 656 (26·8%), including features reporting HRD (298 [12·2%] total cases and 76 [6·3%] ER-positive, HER2-negative cases), highly individualised driver events, mutations underpinning resistance to endocrine therapy, and mutational signatures indicating therapeutic vulnerabilities. 373 (15·2%) cases had WGS features with potential for translational research, including compromised base excision repair and non-homologous end-joining dependency. Structural variation burden (hazard ratio 3·9 [95 CI% 2·4–6·2]; p<0·0001), high levels of APOBEC signatures (2·5 [1·6–4·1]; p<0·0001), and TP53 drivers (3·9 [2·4–6·2]; p<0·0001) were independently prognostic of customary clinical measures (age at diagnosis, stage, and grade) in patients with ER-positive, HER2-negative breast cancer. We developed a prognosticator for ER-positive, HER2-negative breast cancer capable of identifying patients who require either increased intervention or therapy de-escalation, validating the framework in the independent Swedish Cancerome Analysis Network-Breast (SCAN-B) dataset. We show that breast cancer genomes are rich in predictive and prognostic value. We propose a two-step model for effective clinical application. First, the identification of candidates for targeted therapies or clinical trials using highly individualised genomic markers. Second, for patients without such features, the implementation of enhanced prognostication using genomic features alongside existing clinical decision-making factors. National Institute of Health Research, Breast Cancer Research Foundation, Dr Josef Steiner Cancer Research Award 2019, Basser Gray Prime Award 2020, Cancer Research UK, Sir Jeffrey Cheah Early Career Fellowship, the Mats Paulsson Foundation, the Fru Berta Kamprads Foundation, and the Swedish Research Council.

Riboflavin is classified as one of the water-soluble B vitamins. It is part of the functional group of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors and is required for numerous flavoprotein-catalysed reactions. Riboflavin has important antioxidant properties, essential for correct cell functioning. It is required for the conversion of oxidised glutathione to the reduced form and for the mitochondrial respiratory chain as complexes I and II contain flavoprotein reductases and electron transferring flavoproteins. Riboflavin deficiency has been demonstrated to impair the oxidative state of the body, especially in relation to lipid peroxidation status, in both animal and human studies. In the nervous system, riboflavin is essential for the synthesis of myelin and its deficiency can determine the disruption of myelin lamellae. The inherited condition of restricted riboflavin absorption and utilisation, reported in about 10–15% of world population, warrants further investigation in relation to its association with the main neurodegenerative diseases. Several successful trials testing riboflavin for migraine prevention were performed, and this drug is currently classified as a Level B medication for migraine according to the American Academy of Neurology evidence-based rating, with evidence supporting its efficacy. Brown–Vialetto–Van Laere syndrome and Fazio–Londe diseases are now renamed as “riboflavin transporter deficiency” because these are autosomal recessive diseases caused by mutations of SLC52A2 and SLC52A3 genes that encode riboflavin transporters. High doses of riboflavin represent the mainstay of the therapy of these diseases and high doses of riboflavin should be rapidly started as soon as the diagnosis is suspected and continued lifelong. Remarkably, some mitochondrial diseases respond to supplementation with riboflavin. These include multiple acyl-CoA-dehydrogenase deficiency (which is caused by ETFDH gene mutations in the majority of the cases, or mutations in the ETFA and ETFB genes in a minority), mutations of ACAD9 gene, mutations of AIFM1 gene, mutations of the NDUFV1 and NDUFV2 genes. Therapeutic riboflavin administration has been tried in other neurological diseases, including stroke, multiple sclerosis, Friedreich’s ataxia and Parkinson’s disease. Unfortunately, the design of these clinical trials was not uniform, not allowing to accurately assess the real effects of this molecule on the disease course. In this review we analyse the properties of riboflavin and its possible effects on the pathogenesis of different neurological diseases, and we will review the current indications of this vitamin as a therapeutic intervention in neurology.

I n the context of an adequate health care organization, the figure of the neurologist as an emergency operator (in the emergency room—ER—and/or in a dedicated outpatient clinic) is crucial for an effective functional connection with the territory (and therefore with general practitioners), a reduction in inappropriate ER accesses, specific diagnostic and therapeutic approaches to neurological emergencies in the ER and a reduction in nonspecific or even unnecessary instrumental investigations. In this position paper of the Italian Association of Emergency Neurology (ANEU: Associazione Neurologia dell’Emergenza Urgenza), these issues are addressed, and two important organizational solutions are proposed:The Neuro Fast Track, as an outpatient organization approach strongly linked to general practitioners and non-neurological specialists and dedicated to cases with deferrable urgency (to be assessed within 72 h)The identification of an emergency neurologist, who is engaged in ER assessments as a consultant and involved in the management of the semi-intensive care unit of the emergency neurology and the stroke unit according to an appropriate rotation, as well as in consultations for patients with neurological emergencies in inpatient wardsThe possibility of computerizing the screening of patients with deferrable urgency in the Neuro Fast Track is described. A dedicated app represents an important tool that can facilitate the identification of patients for whom deferred assessment is appropriate, the scheduling of neurological examinations and reductions in the booking time through a more rapid approach to specialist assessment and subsequent investigations.

Background and Aim According to randomized controlled trials (RCTs), dual antiplatelet therapy (DAPT) is more effective for secondary prevention of ischemic events attributable to large artery atherosclerosis (LAA) than other mechanisms. We investigated whether real‐world application may impact DAPT effectiveness and safety in the REAl‐life study on short‐term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack (READAPT, NCT05476081). Methods READAPT was an observational multicenter study including patients with minor ischemic stroke or TIA treated with short‐term DAPT. At 90 days, we assessed primary effectiveness (ischemic recurrence, severe bleeding, or vascular death) and safety (severe to moderate bleeding) outcomes. We explored associations between LAA and outcomes using Cox regression. Within patients with and without LAA, outcomes were compared between subgroups based on age, NIHSS score (for ischemic stroke patients), ABCD2 score (for TIA patients), presence and number of MRI acute lesions, and DAPT regimen characteristics. Results Among 1920 analyzed patients (of 2278 enrolled), 452 had LAA. Unlike RCTs, 21.2% of patients with LAA had NIHSS > 5, and 48.2% received DAPT > 30 days. Patients with LAA had higher bleeding rates (3.5% vs. 2.1%, p = 0.004), primarily hemorrhagic infarctions and moderate bleeding, than those without LAA. However, primary effectiveness outcomes were similar (4.9% vs. 3.5%, p = 0.201) between the groups. In patients with LAA, prolonged DAPT (> 21 days), multiple MRI lesions, age ≥ 65, and loading doses increased bleeding risk. Conclusions The real‐world DAPT use in patients with LAA exceeds RCTs boundaries with possible drawbacks on treatment safety.

Background: Dual antiplatelet therapy (DAPT) is a cornerstone of secondary prevention in patients with minor ischemic stroke or high-risk transient ischemic attack. The effectiveness and safety of DAPT may differ between patients with posterior (PCI) and anterior circulation infarct (ACI). Objectives: We aimed to compare short-term outcomes following DAPT between mild-to-moderate stroke patients with PCI versus ACI. Design: Propensity-matched analysis from a prospective real-world multicentric cohort study (READAPT). Methods: We included patients with noncardioembolic mild-to-moderate stroke (National Institute of Health Stroke Scale of 0–10) who initiated DAPT within 48 h of symptom onset. Patients were categorized into ACI or PCI based on the infarct(s) location on brain neuroimaging. The primary effectiveness outcome was the 90-day risk of ischemic stroke or other vascular events. The secondary effectiveness outcomes were the 90-day modified Rankin Scale (mRS) score distribution, 24-h early neurological improvement or deterioration, and all-cause mortality. The safety outcomes included the 90-day risk of any bleedings and 24-h hemorrhagic transformation. Results: We matched 281 PCI patients with 651 ACI patients. The 90-day risk of ischemic stroke or other vascular events was low and similar between PCI and ACI groups (3.1% vs 2.9%, respectively; hazard ratio 0.98, (95% confidence interval (CI) 0.45–2.14); p = 0.845). Patients with PCI had worse 90-day mRS ordinal distribution compared to those with ACI (odds ratio 1.18 (95% CI 1.01–1.39); p = 0.046). There were no differences in other secondary outcomes. Safety outcomes had low incidence and did not differ between groups (any bleedings: 3.2% vs 2.6%; 24-h hemorrhagic transformation: 1.8% vs 1.2%). We found no differences in the risk of ischemic stroke or other vascular events between patients with PCI and ACI across subgroups defined by sex, age, presumed stroke etiology, stroke severity, prestroke mRS, hypertension, diabetes, acute reperfusion therapies, DAPT loading dose, or presence of symptomatic intracranial stenosis. Conclusion: Our findings suggest that effectiveness and safety outcomes after DAPT in patients with mild-to-moderate noncardioembolic ischemic stroke are consistent regardless of infarct location in the anterior or posterior circulation territory. However, patients with PCI may experience worse short-term functional outcome. Trial registration: URL: www.clinicaltrials.gov; Unique identifier: NCT05476081.

Background: Elevated baseline systolic blood pressure (SBP) was associated with poor outcomes following dual antiplatelet therapy (DAPT) in patients with non-cardioembolic minor ischemic stroke (MIS) or high-risk transient ischemic attack (TIA) in clinical trials. Objectives: We aimed to assess the impact of admission SBP on the short-term outcomes after DAPT in patients with non-cardioembolic MIS or high-risk TIA. Methods: We performed an inverse probability weighted (IPW) analysis from a prospective multicentric real-world study (READAPT) including patients with non-cardioembolic MIS (National Institute of Health Stroke Scale of 0–5) or high-risk TIA (ABCD2 ⩾4) who initiated DAPT within 48 h of symptom onset. The primary effectiveness outcome was the 90-day risk of new ischemic stroke or other vascular events. The secondary effectiveness outcomes were the 90-day modified Rankin Scale score ordinal shift, vascular and all-cause mortality, 24-h early neurological improvement or deterioration. The safety outcomes included the 90-day risk of moderate-to-severe and any bleedings, symptomatic intracranial hemorrhage, and 24-h hemorrhagic transformation. We used Cox proportional hazards regression with restricted cubic splines to model the continuous relationship between SBP and the hazard ratio (HR) of new vascular events. We selected SBP = 124 mm Hg as cut-off point for the IPW weighting. Outcomes were compared using Cox and generalized logistic regression analyses, adjusted for residual confounders. Results: From 2278 patients in the READAPT cohort, we included 1291 MIS or high-risk TIAs (mean age 70.6 ± 11.4 years; 65.8% males). After IPW, patients with admission SBP ⩾124 mm Hg versus <124 mm Hg had a significantly higher risk of 90-day ischemic stroke or other vascular events (adjusted HR: 2.14 (95% CI 1.07%–4.98%); p = 0.033) and of 24-h early neurological deterioration (adjusted risk difference: 1.91% (95% CI 0.60%–3.41%); p = 0.006). The overall risk of safety outcomes was low, although patients with SBP ⩾124 mm Hg on admission showed higher rates of 90-day moderate-to-severe and any bleeding events (adjusted risk difference: 1.24% (95% CI 0.38%–2.14%); p = 0.004 and 6.18% (95% CI 4.19%–8.16%); p < 0.001; respectively), as well as of 24-h hemorrhagic transformation (adjusted risk difference: 1.57% (95% CI 0.60%–2.55%); p = 0.001). Subgroup analysis showed a significant interaction between admission SBP, sex, and time to DAPT start in predicting 90-day new vascular events (p for interaction <0.001 and 0.007, respectively). Conclusion: In patients with non-cardioembolic MIS or high-risk TIA, higher levels of admission SBP may be associated with an increased risk of new vascular events, early neurological deterioration, and bleeding after DAPT use. Future studies should further investigate if optimizing blood pressure management may further improve prognosis.

Background Homologous recombination deficiency (HRD) originating from inactivation of genes like BRCA1 / BRCA2 is a targetable abnormality common in triple-negative breast cancer (TNBC). In estrogen-receptor (ER)-positive HER2-negative (ERpHER2n) breast cancer (BC), HRD prevalence and clinical impact are unclear. Methods We analyzed 502 ERpHER2n tumors from patients recruited via the population-representative Swedish SCAN-B study by whole genome sequencing (WGS), defining mutational signatures-based HRD, as well as matched transcriptional, DNA methylation, clinicopathological, adjuvant treatment, and outcome data. Results We show that HRD is much less frequent in ERpHER2n BC (8.4%) compared to TNBC, though induced by similar genetic/epigenetic mechanisms acting on mainly BRCA1 / BRCA2 / RAD51C / PALB2 together, providing a plausible HR-inactivation mechanism for 71.4% of HRD tumors. Our modelled estimate of HRD in Western European/Nordic BC is ~10-13%. HRD tumors were observed across all PAM50 gene expression subtypes with the exception of Luminal A tumors ( < 1%) and did not exhibit a unique, defining transcriptional or DNA methylation profile. While HRD status was not statistically associated with differences in patient outcome for patients treated with combined chemotherapy and endocrine therapy, a nonsignificant trend of poorer outcome for patients with HRD tumors was observed for patients treated with adjuvant endocrine therapy only. Conclusions ERpHER2n HRD tumors show features of aggressive disease, but do not display a distinct transcriptional or DNA methylation profile that clearly differentiates them from HR-proficient tumors. Though numbers are limited, we present early evidence that HRD stratification by WGS could impact therapeutic strategies, as HRD BCs trended to poorer outcomes when not treated with chemotherapy. Plain language summary In this study, we examined the frequency, causes, molecular features, and clinical relevance of homologous recombination (HR) deficiency (HRD) in primary ER-positive/HER2-negative breast cancer using whole-genome sequencing of 502 tumors. HRD was uncommon ( < 10%) and mainly driven by alterations in well-established DNA repair genes, similar to other breast cancer subtypes. HRD tumors did not show clear differences in gene expression or DNA methylation compared with HR-proficient tumors. Clinically, HRD status was not significantly associated with patient outcomes after adjuvant systemic therapy, although patients with HRD tumors treated with endocrine therapy alone showed a trend toward poorer outcomes. Davies, Black et al., investigate the frequency, cause, molecular associations, and prognostic implications of homologous recombination deficiency (HRD) in primary estrogen receptor-positive and HER2-negative breast cancer. HRD was less frequent (8.4%), induced mainly by alterations acting on BRCA1/BRCA2/RAD51C/PALB2, but not associated with patient outcome after adjuvant systemic therapy.

Background Breakthrough ischaemic stroke during oral anticoagulation (OAC) for atrial fibrillation (AF) represents a major therapeutic challenge, especially in patients with cancer, who face competing risks of thrombosis and bleeding. This study investigated the impact of cancer on 90-day outcomes after ischaemic stroke on OAC. Patients and methods We analysed patients with AF who experienced ischaemic stroke while on continuous OAC enrolled in the international retrospective ASPERA-R study, comprising 35 stroke centres across 9 countries. Inverse probability weighting was applied to adjust for baseline imbalances, and weighted Cox, ordinal logistic and generalised linear models were used to estimate adjusted 90-day risks for the primary (ischaemic stroke or TIA), secondary (mRS shift, vascular/all-cause death) and safety (moderate-to-severe bleeding, ICH, 24-h haemorrhagic transformation) outcomes. Results Among 1649 included patients (mean age 78.0 ± 10.7 years; 45.8% male), 247 (15.0%) had cancer, of whom 87 (35.2%) had active cancer and 160 (64.8%) were in remission. After weighting, patients with cancer had a significantly higher 90-day risk of new ischaemic stroke or TIA (8.2% vs 2.8%; adjusted hazard ratio [aHR] 2.56; 95% CI, 1.59–4.13; P < .001) and worse 90-day mRS score distribution (adjusted odds ratio 1.29; 95% CI, 1.08–1.54; P = .005) than those without cancer. Active cancer conferred a > 4-fold higher risk of new ischaemic stroke or TIA (HR 4.48, 95% CI, 2.46–8.13; P < .001) and nearly 3-fold higher risk of moderate-to-severe bleeding (HR 2.77; 95% CI, 1.30–5.88; P = .008). Patients with cancer in remission showed increased ischaemic risk (HR 2.60; 95% CI, 1.59–5.25; P = .001) but not bleeding risk. Haematological malignancies carried a higher risk for both new ischaemic stroke or TIA (HR 3.06; 95% CI, 1.69–5.54; P = .001) and moderate-to-severe bleeding (HR 3.47, 95% CI, 1.57–7.70; P = .006) compared to solid malignancies. Conclusion Cancer, particularly active and haematological malignancies, substantially worsens 90-day prognosis after breakthrough stroke on OAC, underscoring the need for refined risk stratification and tailored secondary prevention. Trial registration URL: www.clinicaltrials.gov; Unique identifier: NCT06823466.

Background: There is only one small single-center study on the reliability of the diagnosis of focal dystonia. The aim of this study was to assess the inter-rater reliability of dystonia diagnosis among neurologists with different professional experience. Methods: Twenty-nine adults (18 with dystonia, 9 with other movement disorders, and 2 healthy controls) were videotaped while undergoing neurological examination and during the process of collecting information on the history of their condition. Each case was diagnosed by 35 blind raters (12 general neurologists, 21 neurology residents, and 2 experts in movement disorders) from different hospitals. Sensitivity and specificity were calculated confronting raters with the gold standard (the caring physician). Inter-rater agreement was measured by the Kappa statistic. Results: Specificity and sensitivity were 95.2 and 66.7%, 76.3 and 75.2%, 84.6 and 71.6% for experts, general neurologists, and residents, respectively. Kappa values on dystonia diagnosis ranged from 0.30 to 0.46. The agreement was moderate for experts and residents (0.40-0.60) and fair for general neurologists (0.20-0.40). Kappas were the highest among experts for cranial and laryngeal dystonia (0.61-1), but not for cervical dystonia (0.37). Conclusions: The diagnosis of dystonia is difficult and only partially mirrors a physician's background. i 2014 S. Karger AG, Basel