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年终盘点:2019年神经内科十大临床研究突破

已有 3512 次阅读 2020-1-6 11:25 |个人分类:神经科学临床和基础|系统分类:科研笔记

2019年神经内科十大临床研究突破


1.N Engl J Med+Lancet—改变指南:最新研究支持卒中后4.5-9小时采取静脉溶栓对某些患者是有益处的

英文摘要1

BACKGROUND:

Strokethrombolysis with alteplase is currently recommended 0-4·5 h after strokeonset. We aimed to determine whether perfusion imaging can identify patientswith salvageable brain tissue with symptoms 4·5 h or more from stroke onset orwith symptoms on waking who might benefit from thrombolysis.

METHODS:

Inthis systematic review and meta-analysis of individual patient data, wesearched PubMed for randomised trials published in English between Jan 1, 2006,and March 1, 2019. We also reviewed the reference list of a previous systematicreview of thrombolysis and searched ClinicalTrials.gov for interventionalstudies of ischaemic stroke. Studies of alteplase versus placebo in patients(aged 18years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-upstroke, who were imaged with perfusion-diffusion MRI or CT perfusion wereeligible for inclusion. The primary outcome was excellent functional outcome(modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline ageand clinical severity. Safety outcomes were death and symptomatic intracerebralhaemorrhage. We calculated odds ratios, adjusted for baseline age and NationalInstitutes of Health Stroke Scale score, using mixed-effects logisticregression models. This study is registered with PROSPERO, numberCRD42019128036.

FINDINGS:

Weidentified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND,and EPITHET. Of the 414 patients included in the three trials, 213 (51%) wereassigned to receive alteplase and 201 (49%) were assigned to receive placebo.Overall, 211 patients in the alteplase group and 199 patients in the placebogroup had mRS assessment data at 3 months and thus were included in theanalysis of the primary outcome. 76 (36%) of 211 patients in the alteplasegroup and 58 (29%) of 199 patients in the placebo group had achieved excellentfunctional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common inthe alteplase group than the placebo group (ten [5%] of 213 patients vs one[<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18(9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96,p=0·66).

INTERPRETATION:

Patientswith ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke withsalvageable brain tissue who were treated with alteplase achieved betterfunctional outcomes than did patients given placebo. The rate of symptomaticintracerebral haemorrhage was higher with alteplase, but this increase did notnegate the overall net benefit of thrombolysis.

英文摘要2

BACKGROUND:

Thetime to initiate intravenous thrombolysis for acute ischemic stroke isgenerally limited to within 4.5 hours after the onset of symptoms. Some trialshave suggested that the treatment window may be extended in patients who areshown to have ischemic but not yet infarcted brain tissue on imaging.

METHODS:

Weconducted a multicenter, randomized, placebo-controlled trial involvingpatients with ischemic stroke who had hypoperfused but salvageable regions ofbrain detected on automated perfusion imaging. The patients were randomlyassigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hoursafter the onset of stroke or on awakening with stroke (if within 9 hours fromthe midpoint of sleep). The primary outcome was a score of 0 or 1 on themodified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death),at 90 days. The risk ratio for the primary outcome was adjusted for age andclinical severity at baseline.

RESULTS:

After225 of the planned 310 patients had been enrolled, the trial was terminatedbecause of a loss of equipoise after the publication of positive results from aprevious trial. A total of 113 patients were randomly assigned to the alteplasegroup and 112 to the placebo group. The primary outcome occurred in 40 patients(35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group(adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06;P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%)in the alteplase group and in 1 patient (0.9%) in the placebo group (adjustedrisk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysisof the distribution of scores on the modified Rankin scale did not show asignificant between-group difference in functional improvement at 90 days.

CONCLUSIONS:

Amongthe patients in this trial who had ischemic stroke and salvageable braintissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or atthe time the patient awoke with stroke symptoms resulted in a higher percentageof patients with no or minor neurologic deficits than the use of placebo. Therewere more cases of symptomatic cerebral hemorrhage in the alteplase group thanin the placebo group. (Funded by the Australian National Health and MedicalResearch Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 andNCT01580839.).

参考文献:

1.Campbell et al (2019). Extending thrombolysis to 4·5-9 h and wake-up strokeusing perfusion imaging: a systematic review and meta-analysis of individualpatient data. Lancet. 2019 Jul 13;394(10193):139-147.

2.Ma et al (2019). Thrombolysis Guided by Perfusion Imaging up to 9 Hours afterOnset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803.

 

2.N Engl J Med+Lancet— 人源化抗CGRP抗体或者CGRP阻断剂防治偏头痛取得较好疗效

英文摘:1

BACKGROUND:

Antibodiestargeting calcitonin gene-related peptide (CGRP) or its receptor have shownefficacy in the prevention of migraine attacks. We investigated the efficacyand tolerability of fremanezumab, a fully humanised CGRP antibody, in patientswith migraine who had previously not responded to two to four classes ofmigraine preventive medications.

METHODS:

Therandomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUStrial was done at 104 sites (including hospitals, medical centres, researchinstitutes, and group practice clinics) across Belgium, the Czech Republic,Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain,Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70years with episodic or chronic migraine who had documented failure to two tofour classes of migraine preventive medications in the past 10 years. Failurewas defined as no clinically meaningful improvement after at least 3 months oftherapy at a stable dose, as per the treating physician's judgment;discontinuation because of adverse events that made treatment intolerable; ortreatment contraindicated or unsuitable for the preventive treatment ofmigraine for the patient. Participants were randomly assigned (1:1:1) byelectronic interactive response technology to subcutaneously administeredquarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthlyfremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronicmigraine; months 2 and 3: 225 mg in both migraine subgroups), or matchedmonthly placebo for 12 weeks. The primary outcome was mean change from baselinein the monthly average number of migraine days during the 12-week treatmentperiod. This trial is registered with ClinicalTrials.gov, number NCT03308968,and is now completed.

FINDINGS:

BetweenNov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) orchronic (509 [61%]) migraine were randomly assigned to placebo (n=279),quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductionsfrom baseline in monthly average migraine days over 12 weeks were greaterversus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterlyfremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI-3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1[0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverseevents were similar for placebo and fremanezumab. Serious adverse events werereported in four (1%) of 277 participants with placebo, two (<1%) of 276with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab.

INTERPRETATION:

Fremanezumabwas effective and well tolerated in patients with difficult-to-treat migrainewho had previously not responded to up to four classes of migraine preventivemedications.

英文摘要2

BACKGROUND:

Rimegepant,a small molecule calcitonin gene-related peptide receptor antagonist, has shownefficacy in the acute treatment of migraine using a standard tabletformulation. The objective of this trial was to compare the efficacy, safety,and tolerability of a novel orally disintegrating tablet formulation ofrimegepant at 75 mg with placebo in the acute treatment of migraine.

METHODS:

Inthis double-blind, randomised, placebo-controlled, multicentre phase 3 trial,adults aged 18 years or older with history of migraine of at least 1 year wererecruited to 69 study centres in the USA. Participants were randomly assignedto receive rimegepant (75 mg orally disintegrating tablet) or placebo andinstructed to treat a single migraine attack of moderate or severe painintensity. The randomisation was stratified by the use of prophylacticmedication (yes or no), and was carried out using an interactive web responsesystem that was accessed by each clinical site. All participants,investigators, and the sponsor were masked to treatment group assignment. Thecoprimary endpoints were freedom from pain and freedom from the most bothersomesymptom at 2 h postdose. The efficacy analyses used the modifiedintention-to-treat population, which included all patients who were randomlyassigned, had a migraine attack with pain of moderate or severe intensity, tooka dose of rimegepant or placebo, and had at least one efficacy assessment afteradministration of the dose. The safety analyses included all randomly assignedparticipants who received at least one dose of study medication. This study isregistered with ClinicalTrials.gov, number NCT03461757, and is closed toaccrual.

FINDINGS:

BetweenFeb 27 and Aug 28, 2018, 1811 participants were recruited and assessed foreligibility. 1466 participants were randomly assigned to the rimegepant (n=732)or placebo (n=734) groups, of whom 1375 received treatment with rimegepant(n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepantn=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tabletwas superior to placebo for freedom from pain (21% vs 11%, p<0·0001; riskdifference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35%vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverseevents were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinarytract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant ineach treatment group had a transaminase concentration of more than 3 × theupper limit of normal; neither was related to study medication, and noelevations in bilirubin greater than 2 × the upper limit of normal werereported. Treated participants reported no serious adverse events.

INTERPRETATION:

Inthe acute treatment of migraine, a single 75 mg dose of rimegepant in an orallydisintegrating tablet formulation was more effective than placebo. Tolerabilitywas similar to placebo, with no safety concerns.

英文摘要3

BACKGROUND:

Calcitoningene-related peptide receptor has been implicated in the pathogenesis ofmigraine. Rimegepant is an orally administered, small-molecule, calcitoningene-related peptide receptor antagonist that may be effective in acutemigraine treatment.

METHODS:

In amulticenter, double-blind, phase 3 trial, we randomly assigned adults with atleast a 1-year history of migraine and two to eight migraine attacks ofmoderate or severe intensity per month to receive rimegepant orally at a doseof 75 mg or matching placebo for the treatment of a single migraine attack. Theprimary end points were freedom from pain and freedom from the most bothersomesymptom (other than pain) identified by the patient, both of which wereassessed 2 hours after the dose of rimegepant or placebo was administered.

RESULTS:

Atotal of 1186 patients were randomly assigned to receive rimegepant (594patients) or placebo (592 patients); of these, 537 patients in the rimegepantgroup and 535 patients in the placebo group could be evaluated for efficacy.The overall mean age of the patients evaluated for efficacy was 40.6 years, and88.7% were women. In a modified intention-to-treat analysis, the percentage ofpatients who were pain-free 2 hours after receiving the dose was 19.6% in therimegepant group and 12.0% in the placebo group (absolute difference, 7.6percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). Thepercentage of patients who were free from their most bothersome symptom 2 hoursafter the dose was 37.6% in the rimegepant group and 25.2% in the placebo group(absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001).The most common adverse events were nausea and urinary tract infection.

CONCLUSIONS:

Treatmentof a migraine attack with the oral calcitonin gene-related peptide receptorantagonist rimegepant resulted in a higher percentage of patients who were freeof pain and free from their most bothersome symptom than placebo. (Funded byBiohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

参考文献:

1.Ferrari et al (2019). Fremanezumab versus placebo for migraine prevention inpatients with documented failure to up to four migraine preventive medicationclasses (FOCUS): a randomised, double-blind, placebo-controlled, phase 3btrial. Lancet. 2019 Sep 21;394(10203):1030-1040.

2.Croop et al (2019). Efficacy, safety, and tolerability of rimegepant orallydisintegrating tablet for the acute treatment of migraine: a randomised, phase3, double-blind, placebo-controlled trial. Lancet. 2019 Aug31;394(10200):737-745.

3.Lipton et al (2019). Rimegepant, an Oral Calcitonin Gene-Related PeptideReceptor Antagonist, for Migraine. N Engl J Med. 2019 Jul 11;381(2):142-149.

 

3. N Engl J Med+Lancet—IL-6R抗体和抗CD19抗体治疗视神经脊髓炎谱系疾病取得较好疗效

英文摘要1

Abstract

BACKGROUND:

Neuromyelitisoptica spectrum disorder (NMOSD) is an autoimmune disease of the centralnervous system and is associated with autoantibodies to anti-aquaporin-4(AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involvedin the pathogenesis of the disorder. Satralizumab is a humanized monoclonalantibody targeting the interleukin-6 receptor. The efficacy of satralizumab addedto immunosuppressant treatment in patients with NMOSD is unclear.

METHODS:

In aphase 3, randomized, double-blind, placebo-controlled trial, we randomlyassigned, in a 1:1 ratio, patients with NMOSD who were seropositive orseronegative for AQP4-IgG to receive either satralizumab, at a dose of 120 mg,or placebo, administered subcutaneously at weeks 0, 2, and 4 and every 4 weeksthereafter, added to stable immunosuppressant treatment. The primary end pointwas the first protocol-defined relapse in a time-to-event analysis. Keysecondary end points were the change from baseline to week 24 in thevisual-analogue scale (VAS) pain score (range, 0 to 100, with higher scoresindicating more pain) and the Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F) score (range, 0 to 52, with lower scores indicatingmore fatigue). Safety was also assessed.

RESULTS:

Atotal of 83 patients were enrolled, with 41 assigned to the satralizumab groupand 42 to the placebo group. The median treatment duration with satralizumab inthe double-blind period was 107.4 weeks. Relapse occurred in 8 patients (20%)receiving satralizumab and in 18 (43%) receiving placebo (hazard ratio, 0.38;95% confidence interval [CI], 0.16 to 0.88). Multiple imputation for censoreddata resulted in hazard ratios ranging from 0.34 to 0.44 (with corresponding Pvalues of 0.01 to 0.04). Among 55 AQP4-IgG-seropositive patients, relapseoccurred in 11% of those in the satralizumab group and in 43% of those in theplacebo group (hazard ratio, 0.21; 95% CI, 0.06 to 0.75); among 28AQP4-IgG-seronegative patients, relapse occurred in 36% and 43%, respectively(hazard ratio, 0.66; 95% CI, 0.20 to 2.24). The between-group difference in thechange in the mean VAS pain score was 4.08 (95% CI, -8.44 to 16.61); thebetween-group difference in the change in the mean FACIT-F score was -3.10 (95%CI, -8.38 to 2.18). The rates of serious adverse events and infections did notdiffer between groups.

CONCLUSIONS:

Amongpatients with NMOSD, satralizumab added to immunosuppressant treatment led to alower risk of relapse than placebo but did not differ from placebo in its effecton pain or fatigue. (Funded by Chugai Pharmaceutical; ClinicalTrials.govnumber, NCT02028884.).

英文摘要2

BACKGROUND:

Noapproved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), arare, relapsing, autoimmune, inflammatory disease of the CNS that causesblindness and paralysis. We aimed to assess the efficacy and safety ofinebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk ofattacks and disability in NMOSD.

METHODS:

Wedid a multicentre, double-blind, randomised placebo-controlled phase 2/3 studyat 99 outpatient specialty clinics or hospitals in 25 countries. Eligibleparticipants were adults (18years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale scoreof 8·0 or less, and a history of at least one attack requiring rescue therapyin the year before screening or at least two attacks requiring rescue therapyin the 2 years before screening. Participants were randomly allocated (3:1) to300 mg intravenous inebilizumab or placebo with a central interactive voiceresponse system or interactive web response system and permuted blockrandomisation. Inebilizumab or placebo was administered on days 1 and 15.Participants, investigators, and all clinical staff were masked to thetreatments, and inebilizumab and placebo were indistinguishable in appearance.The primary endpoint was time to onset of an NMOSD attack, as determined by theadjudication committee. Efficacy endpoints were assessed in all randomlyallocated patients who received at least one dose of study intervention, andsafety endpoints were assessed in the as-treated population. The study isregistered with ClinicalTrials.gov, number NCT02200770.

FINDINGS:

BetweenJan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned totreatment and dosed, with 174 participants receiving inebilizumab and 56receiving placebo. The randomised controlled period was stopped before completeenrolment, as recommended by the independent data-monitoring committee, becauseof a clear demonstration of efficacy. 21 (12%) of 174 participants receivinginebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo(hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurredin 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56participants receiving placebo. Serious adverse events occurred in eight (5%)of 174 participants receiving inebilizumab and five (9%) of 56 participantsreceiving placebo.

INTERPRETATION:

Comparedwith placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumabhas potential application as an evidence-based treatment for patients withNMOSD.

参考文献:

1.Yamamura et al (2019). Trial of Satralizumab in Neuromyelitis Optica SpectrumDisorder. N Engl J Med. 2019 Nov 28;381(22):2114-2124.

2.Cree et al (2019). Inebilizumab for the treatment of neuromyelitis opticaspectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlledphase 2/3 trial. Lancet. 2019 Oct 12;394(10206):1352-1363.

 

4.N Engl J Med—专家实现个性化设计寡核苷酸药物以治疗罕见遗传疾病

英文摘要:

Genomesequencing is often pivotal in the diagnosis of rare diseases, but many ofthese conditions lack specific treatments. We describe how molecular diagnosisof a rare, fatal neurodegenerative condition led to the rational design,testing, and manufacture of milasen, a splice-modulating antisenseoligonucleotide drug tailored to a particular patient. Proof-of-conceptexperiments in cell lines from the patient served as the basis for launching an"N-of-1" study of milasen within 1 year after first contact with thepatient. There were no serious adverse events, and treatment was associatedwith objective reduction in seizures (determined by electroencephalography andparental reporting). This study offers a possible template for the rapiddevelopment of patient-customized treatments. (Funded by Mila's MiracleFoundation and others.).

参考文献:

Kimet al (2019). Patient-Customized Oligonucleotide Therapy for a Rare GeneticDisease. N Engl J Med. 2019 Oct 24;381(17):1644-1652.

 

5.N Engl J Med—抑制HTT mRNA的反义寡核苷酸药物治疗亨廷顿病安全性良好(临床试验1-2a)

英文摘要:

BACKGROUND:

Huntington'sdisease is an autosomal-dominant neurodegenerative disease caused by CAGtrinucleotide repeat expansion in HTT, resulting in a mutant huntingtinprotein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotidedesigned to inhibit HTT messenger RNA and thereby reduce concentrations ofmutant huntingtin.

METHODS:

Weconducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trialinvolving adults with early Huntington's disease. Patients were randomlyassigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecaladministration every 4 weeks for four doses. Dose selection was guided by apreclinical model in mice and nonhuman primates that related dose level toreduction in the concentration of huntingtin. The primary end point was safety.The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid(CSF). Prespecified exploratory end points included the concentration of mutanthuntingtin in CSF.

RESULTS:

Ofthe 46 patients who were enrolled in the trial, 34 were randomly assigned toreceive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomlyassigned to receive placebo. Each patient received all four doses and completedthe trial. Adverse events, all of grade 1 or 2, were reported in 98% of thepatients. No serious adverse events were seen in HTTRx-treated patients. Therewere no clinically relevant adverse changes in laboratory variables. Predose(trough) concentrations of HTTRx in CSF showed dose dependence up to doses of60 mg. HTTRx treatment resulted in a dose-dependent reduction in theconcentration of mutant huntingtin in CSF (mean percentage change frombaseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in theHTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).

CONCLUSIONS:

Intrathecaladministration of HTTRx to patients with early Huntington's disease was notaccompanied by serious adverse events. We observed dose-dependent reductions inconcentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F.Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).

参考文献:

Tabriziet al (2019). Targeting Huntingtin Expression in Patients with Huntington'sDisease. N Engl J Med. 2019 Jun 13;380(24):2307-2316.

 

6.Nature—肿瘤疫苗研发新突破:新抗原靶向疫苗可募集T细胞免疫以对抗神经胶质瘤

英文摘要:

Neoantigens,which are derived from tumour-specific protein-coding mutations, are exemptfrom central tolerance, can generate robust immune responses1,2 andcan function as bona fide antigens that facilitate tumour rejection3.Here we demonstrate that a strategy that uses multi-epitope, personalizedneoantigen vaccination, which has previously been tested in patients withhigh-risk melanoma4-6, is feasible for tumours such as glioblastoma,which typically have a relatively low mutation load1,7 and animmunologically 'cold' tumour microenvironment8. We usedpersonalized neoantigen-targeting vaccines to immunize patients newly diagnosedwith glioblastoma following surgical resection and conventional radiotherapy ina phase I/Ib study. Patients who did not receive dexamethasone-a highly potentcorticosteroid that is frequently prescribed to treat cerebral oedema inpatients with glioblastoma-generated circulating polyfunctionalneoantigen-specific CD4+ and CD8+ T cell responses thatwere enriched in a memory phenotype and showed an increase in the number oftumour-infiltrating T cells. Using single-cell T cell receptor analysis, weprovide evidence that neoantigen-specific T cells from the peripheral blood canmigrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccinesthus have the potential to favourably alter the immune milieu of glioblastoma.

参考文献:

Keskinet al (2019). Neoantigen vaccine generates intratumoral T cell responses inphase Ib glioblastoma trial. Nature. 2019 Jan;565(7738):234-239.

 

7.Nat Med—PD-1抗体可改善复发性神经胶质瘤的总体生存率

英文摘要1

Glioblastomais the most common primary malignant brain tumor in adults and is associatedwith poor survival. The Ivy Foundation Early Phase Clinical Trials Consortiumconducted a randomized, multi-institution clinical trial to evaluate immuneresponses and survival following neoadjuvant and/or adjuvant therapy withpembrolizumab in 35 patients with recurrent, surgically resectableglioblastoma. Patients who were randomized to receive neoadjuvantpembrolizumab, with continued adjuvant therapy following surgery, hadsignificantly extended overall survival compared to patients that wererandomized to receive adjuvant, post-surgical programmed cell death protein 1(PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated withupregulation of T cell- and interferon-γ-related gene expression, butdownregulation of cell-cycle-related gene expression within the tumor, whichwas not seen in patients that received adjuvant therapy alone. Focal inductionof programmed death-ligand 1 in the tumor microenvironment, enhanced clonalexpansion of T cells, decreased PD-1 expression on peripheral blood T cells anda decreasing monocytic population was observed more frequently in theneoadjuvant group than in patients treated only in the adjuvant setting. Thesefindings suggest that the neoadjuvant administration of PD-1 blockade enhancesboth the local and systemic antitumor immune response and may represent a moreefficacious approach to the treatment of this uniformly lethal brain tumor.

英文摘要2

Immunecheckpoint inhibitors have been successful across several tumor types; however,their efficacy has been uncommon and unpredictable in glioblastomas (GBM),where <10% of patients show long-term responses. To understand the moleculardeterminants of immunotherapeutic response in GBM, we longitudinally profiled66 patients, including 17 long-term responders, during standard therapy andafter treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic andtranscriptomic analysis revealed a significant enrichment of PTEN mutationsassociated with immunosuppressive expression signatures in non-responders, andan enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders.Responsive tumors were also associated with branched patterns of evolution fromthe elimination of neoepitopes as well as with differences in T cell clonaldiversity and tumor microenvironment profiles. Our study shows that clinicalresponse to anti-PD-1 immunotherapy in GBM is associated with specificmolecular alterations, immune expression signatures, and immune infiltrationthat reflect the tumor's clonal evolution during treatment.

参考文献:

1.Cloughesyet al (2019). Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefitwith intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019 Mar;25(3):477-486.

2.Zhao et al (2019). Immune and genomic correlates of response to anti-PD-1immunotherapy in glioblastoma. Nat Med. 2019 Mar;25(3):462-469.

 

8.JAMA—强效降压相比于常规降压可显著减少脑白质损伤但是不能降低痴呆患病率

英文摘要1

Importance:

Theeffect of intensive blood pressure lowering on brain health remains uncertain.

Objective:

Toevaluate the association of intensive blood pressure treatment with cerebralwhite matter lesion and brain volumes.

Design,Setting, and Participants:

Asubstudy of a multicenter randomized clinical trial of hypertensive adults 50years or older without a history of diabetes or stroke at 27 sites in theUnited States. Randomization began on November 8, 2010. The overall trial wasstopped early because of benefit for its primary outcome (a composite ofcardiovascular events) and all-cause mortality on August 20, 2015. Brainmagnetic resonance imaging (MRI) was performed on a subset of participants atbaseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up datewas July 1, 2016.

Interventions:

Participantswere randomized to a systolic blood pressure (SBP) goal of either less than 120mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standardtreatment, n = 315).

MainOutcomes and Measures:

Theprimary outcome was change in total white matter lesion volume from baseline.Change in total brain volume was a secondary outcome.

Results:

Among670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years;40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 yearsafter randomization, after a median intervention period of 3.40 years. In theintensive treatment group, based on a robust linear mixed model, mean whitematter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95%CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3[95% CI, 1.21 to 1.70]) in the standard treatment group (between-groupdifference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brainvolume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI,-32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standardtreatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to-1.1]).

Conclusionsand Relevance:

Amonghypertensive adults, targeting an SBP of less than 120 mm Hg, compared withless than 140 mm Hg, was significantly associated with a smaller increase incerebral white matter lesion volume and a greater decrease in total brainvolume, although the differences were small.

英文摘要2

Importance: Thereare currently no proven treatments to reduce the risk of mild cognitiveimpairment and dementia.

Objective: Toevaluate the effect of intensive blood pressure control on risk of dementia.

Design,Setting, and Participants: Randomizedclinical trial conducted at 102 sites in the United States and Puerto Ricoamong adults aged 50 years or older with hypertension but without diabetes orhistory of stroke. Randomization began on November 8, 2010. The trial wasstopped early for benefit on its primary outcome (a composite of cardiovascularevents) and all-cause mortality on August 20, 2015. The final date for follow-upof cognitive outcomes was July 22, 2018.

Interventions:

Participantswere randomized to a systolic blood pressure goal of either less than 120 mm Hg(intensive treatment group; n = 4678) or less than 140 mm Hg (standardtreatment group; n = 4683).

MainOutcomes and Measures: Theprimary cognitive outcome was occurrence of adjudicated probable dementia.Secondary cognitive outcomes included adjudicated mild cognitive impairment anda composite outcome of mild cognitive impairment or probable dementia.

Results: Among9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563(91.5%) completed at least 1 follow-up cognitive assessment. The medianintervention period was 3.34 years. During a total median follow-up of 5.11years, adjudicated probable dementia occurred in 149 participants in theintensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04).Intensive BP control significantly reduced the risk of mild cognitiveimpairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI,0.69-0.95) and the combined rate of mild cognitive impairment or probabledementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI,0.74-0.97).

Conclusionsand Relevance: Amongambulatory adults with hypertension, treating to a systolic blood pressure goalof less than 120 mm Hg compared with a goal of less than 140 mm Hg did notresult in a significant reduction in the risk of probable dementia. Becauseof early study termination and fewer than expected cases of dementia, the studymay have been underpowered for this end point.

参考文献:

1.SPRINTMIND Investigators for the SPRINT Research Group. Association of Intensive vsStandard Blood Pressure Control With Cerebral White Matter Lesions. JAMA. 2019Aug 13;322(6):524-534.

2.SPRINTMIND Investigators for the SPRINT Research Group. Effect of Intensive vsStandard Blood Pressure Control on Probable Dementia: A Randomized ClinicalTrial. JAMA. 2019 Feb 12;321(6):553-561.

 

9.N Engl J Med—左乙拉西坦、磷苯妥英和丙戊酸钠可用于缓解癫痫持续状态

英文摘要:

BACKGROUND:

Thechoice of drugs for patients with status epilepticus that is refractory totreatment with benzodiazepines has not been thoroughly studied.

METHODS:

In arandomized, blinded, adaptive trial, we compared the efficacy and safety ofthree intravenous anticonvulsive agents - levetiracetam, fosphenytoin, andvalproate - in children and adults with convulsive status epilepticus that wasunresponsive to treatment with benzodiazepines. The primary outcome was absenceof clinically evident seizures and improvement in the level of consciousness by60 minutes after the start of drug infusion, without additional anticonvulsantmedication. The posterior probabilities that each drug was the most or leasteffective were calculated. Safety outcomes included life-threateninghypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence,and death.

RESULTS:

Atotal of 384 patients were enrolled and randomly assigned to receivelevetiracetam (145 patients), fosphenytoin (118), or valproate (121).Reenrollment of patients with a second episode of status epilepticus accountedfor 16 additional instances of randomization. In accordance with a prespecifiedstopping rule for futility of finding one drug to be superior or inferior, aplanned interim analysis led to the trial being stopped. Of the enrolledpatients, 10% were determined to have had psychogenic seizures. The primaryoutcome of cessation of status epilepticus and improvement in the level ofconsciousness at 60 minutes occurred in 68 patients assigned to levetiracetam(47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin(45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate(46%; 95% credible interval, 38 to 55). The posterior probability that eachdrug was the most effective was 0.41, 0.24, and 0.35, respectively. Numericallymore episodes of hypotension and intubation occurred in the fosphenytoin groupand more deaths occurred in the levetiracetam group than in the other groups,but these differences were not significant.

CONCLUSIONS:

Inthe context of benzodiazepine-refractory convulsive status epilepticus, theanticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led toseizure cessation and improved alertness by 60 minutes in approximately halfthe patients, and the three drugs were associated with similar incidences ofadverse events. (Funded by the National Institute of Neurological Disorders andStroke; ESETT ClinicalTrials.gov number, NCT01960075.).

参考文献:

Kapuret al (2019). Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113.

 

10.N Engl J Med—机器学习可识别急性脑外伤后临床无反应患者有无大脑的激活

英文摘要:

BACKGROUND:

Brainactivation in response to spoken motor commands can be detected byelectroencephalography (EEG) in clinically unresponsive patients. Theprevalence and prognostic importance of a dissociation between commanded motorbehavior and brain activation in the first few days after brain injury are notwell understood.

METHODS:

Westudied a prospective, consecutive series of patients in a single intensivecare unit who had acute brain injury from a variety of causes and who wereunresponsive to spoken commands, including some patients with the ability tolocalize painful stimuli or to fixate on or track visual stimuli. Machinelearning was applied to EEG recordings to detect brain activation in responseto commands that patients move their hands. The functional outcome at 12 monthswas determined with the Glasgow Outcome Scale-Extended (GOS-E; levels rangefrom 1 to 8, with higher levels indicating better outcomes).

RESULTS:

Atotal of 16 of 104 unresponsive patients (15%) had brain activation detected byEEG at a median of 4 days after injury. The condition in 8 of these 16 patients(50%) and in 23 of 88 patients (26%) without brain activation improved suchthat they were able to follow commands before discharge. At 12 months, 7 of 16patients (44%) with brain activation and 12 of 84 patients (14%) without brainactivation had a GOS-E level of 4 or higher, denoting the ability to functionindependently for 8 hours (odds ratio, 4.6; 95% confidence interval, 1.2 to17.1).

CONCLUSIONS:

Adissociation between the absence of behavioral responses to motor commands andthe evidence of brain activation in response to these commands in EEGrecordings was found in 15% of patients in a consecutive series of patientswith acute brain injury. (Supported by the Dana Foundation and the James S.McDonnell Foundation.).

参考文献:

Claassenet al (2019). Detection of Brain Activation in Unresponsive Patients with AcuteBrain Injury. NEngl J Med. 2019 Jun 27;380(26):2497-2505.

2019年十大研究进展名录

1. 年终盘点:2019年帕金森病十大基础研究进展

2. 年终盘点:2019年帕金森病十大临床研究进展

3. 年终盘点:2019年阿尔茨海默病十大基础研究进展

4. 年终盘点:2019年阿尔茨海默病十大临床研究进展

5. 年终盘点:2019年神经科学领域十大基础研究进展

6. 年终盘点:2019年抑郁症领域十大基础研究进展(一半来自中国)

7. 年终盘点:2019年脑血管病领域十大基础研究进展

8. 年终盘点:2019年神经炎症领域十大基础研究进展

9. 年终盘点:2019年神经活动记录十大基础研究进展

10. 年终盘点:2019年ALS/FTD十大基础研究进展

11. 年终盘点:2019年医学和生物学领域深度学习和神经网络十大基础研究进展


2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症(ALS)十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破


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20个神经科学领域的突破可能获得诺贝尔奖

1. 意识研究:意识的本质、组成、运行机制及其物质载体;不同意识层次的操控和干预,意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控:记忆的形成和消退机制,记忆的人为移植和记忆的人为消除等;

3. 痴呆研究:阿尔茨海默病的机制和治疗研究,血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究:喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究:性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究,包括脑卒中、脊髓损伤机制研究,神经干细胞移植研究,新型神经修复技术,神经康复技术。

13. 精神类疾病的机制和干预研究:自闭症、精分、抑郁症、智能障碍、药物成瘾等;

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究,包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术:光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究,包括脑机接口、神经刺激芯片、记忆存储芯片,意识存储芯片,人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术:包括任何机械肢体的人类移植,大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术:高分辨率成像技术、大型电极微阵列技术等。





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