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PURPOSE: Chronic idiopathic urinary retention (CIUR) in young women is poorly understood and a probable etiology is established only in around 40%, most commonly a primary disorder of external urethral sphincter relaxation, sometimes referred to as Fowler's syndrome. A high prevalence of psychological and functional comorbidities is reported, however these have been poorly characterized. MATERIALS AND METHODS: Women consecutively referred for the assessment and management of CIUR were evaluated cross-sectionally for 13 psychological/behavioral domains using a structured clinical interview: depression, anxiety, post-traumatic stress disorder (PTSD), other psychiatric history, functional neurological disorder, other functional syndromes, childhood and adult trauma, personality disorder, and self-harm (ever/current). RESULTS: A total of 91 women (mean age [SD]: 34 [11] years) were evaluated. Women with Fowler's syndrome (n = 69) were younger (mean age [SD]: 32 [9] vs 40 [13] years) than women without Fowler's syndrome and reported shorter mean duration of urinary symptoms (mean [SD]: 5 [6] vs 10 [9]). A high prevalence of psychiatric and psychological comorbidities was reported (97%) including current depression (77%), current anxiety (78%), and PTSD (32%). A high prevalence of functional neurological disorder (56%) and other functional symptoms (65%) was also reported. Self-harm was reported in (14%) and personality disorder in 16%. Childhood trauma was reported in 35% of women. CONCLUSIONS: Young women with CIUR report a high burden of psychiatric disorders, affective symptoms, trauma, PTSD, self-harm, and functional neurological disorder, particularly in those with Fowler's syndrome. These factors can undermine the engagement with health care professionals and affect management and should therefore be addressed during the urological assessment.
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Retenção Urinária , Humanos , Feminino , Retenção Urinária/epidemiologia , Retenção Urinária/psicologia , Adulto , Prevalência , Estudos Transversais , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/psicologia , Transtornos Mentais/epidemiologia , Transtornos Mentais/complicações , Comorbidade , Pessoa de Meia-IdadeRESUMO
Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.
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Patient-reported outcomes (PROs) are increasingly used in healthcare research to provide evidence of the benefits and risks of interventions from the patient perspective and to inform regulatory decisions and health policy. The use of PROs in clinical practice can facilitate symptom monitoring, tailor care to individual needs, aid clinical decision-making and inform value-based healthcare initiatives. Despite their benefits, there are concerns that the potential burden on respondents may reduce their willingness to complete PROs, with potential impact on the completeness and quality of the data for decision-making. We therefore conducted an initial literature review to generate a list of candidate recommendations aimed at reducing respondent burden. This was followed by a two-stage Delphi survey by an international multi-stakeholder group. A consensus meeting was held to finalize the recommendations. The final consensus statement includes 19 recommendations to address PRO respondent burden in healthcare research and clinical practice. If implemented, these recommendations may reduce PRO respondent burden.
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Avaliação de Resultados da Assistência ao Paciente , Medidas de Resultados Relatados pelo Paciente , Humanos , Consenso , Tomada de Decisão ClínicaRESUMO
BACKGROUND: It is unknown whether new daily persistent headache (NDPH) is a single disorder or heterogenous group of disorders, and whether it is a unique disorder from chronic migraine and chronic tension-type headache. We describe a large group of patients with primary NDPH, compare its phenotype to transformed chronic daily headache (T-CDH), and use cluster analysis to reveal potential sub-phenotypes in the NDPH group. METHODS: We performed a case-control study using prospectively collected clinical data in patients with primary NDPH and T-CDH (encompassing chronic migraine and chronic tension-type headache). We used logistic regression with propensity score matching to compare demographics, phenotype, comorbidities, and treatment responses between NDPH and T-CDH. We used K-means cluster analysis with Gower distance to identify sub-clusters in the NDPH group based on a combination of demographics, phenotype, and comorbidities. RESULTS: We identified 366 patients with NDPH and 696 with T-CDH who met inclusion criteria. Patients with NDPH were less likely to be female (62.6% vs. 73.3%, p < 0.001). Nausea, vomiting, photophobia, phonophobia, motion sensitivity, vertigo, and cranial autonomic symptoms were all significantly less frequent in NDPH than T-CDH (p value for all < 0.001). Acute treatments appeared less effective in NDPH than T-CDH, and medication overuse was less common (16% vs. 42%, p < 0.001). Response to most classes of oral preventive treatments was poor in both groups. The most effective treatment in NDPH was doselupin in 45.7% patients (95% CI 34.8-56.5%). Cluster analysis identified three subgroups of NDPH. Cluster 1 was older, had a high proportion of male patients, and less severe headaches. Cluster 2 was predominantly female, had severe headaches, and few associated symptoms. Cluster 3 was predominantly female with a high prevalence of migrainous symptoms and headache triggers. CONCLUSIONS: Whilst there is overlap in the phenotype of NDPH and T-CDH, the differences in migrainous, cranial autonomic symptoms, and vulnerability to medication overuse suggest that they are not the same disorder. NDPH may be fractionated into three sub-phenotypes, which require further investigation.
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Transtornos da Cefaleia , Transtornos de Enxaqueca , Cefaleia do Tipo Tensional , Feminino , Masculino , Humanos , Estudos de Casos e Controles , Cefaleia , FenótipoRESUMO
Decentralized clinical trials (DCTs), that is, studies integrating elements of telemedicine and mobile/local healthcare providers allowing for home-based assessments, are an important concept to make studies more resilient and more patient-centric by taking into consideration participant's views and shifting trial activities to better meet the needs of trial participants. There are however, not only advantages but also challenges associated with DCTs. An area to be addressed by appropriate statistical methodology is the integration of data resulting from a possible mix of home and clinic assessments at different visits for the same variable, especially in adjusting for sources of possible systematic differences. One source of systematic bias may be how a participant perceives their disease and treatment in their home versus in a clinical setting. In this paper, we will discuss these issues with a focus on Neuroscience when participants have the choice between home and clinic assessments to illustrate how to identify systematic biases and describe appropriate approaches to maintain clinical trial scientific rigor. We will describe the benefits and challenges of DCTs in Neuroscience and then describe the relevance of home versus clinic assessments using the estimand framework. We outline several options to enable home assessments in a study. Results of simulations will be presented to help deciding between design and analysis options in a simple scenario where there might be differences in response between clinic and home assessments.
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Viés , Ensaios Clínicos como Assunto , HumanosRESUMO
BACKGROUND: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. RESULTS: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONS: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. TRIAL REGISTRATION: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).
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Lista de Checagem , Projetos de Pesquisa , Humanos , Consenso , Reprodutibilidade dos Testes , Relatório de PesquisaRESUMO
INTRODUCTION: Early phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements. METHODS AND ANALYSIS: A methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions. ETHICS AND DISSEMINATION: This project was approved by ICR's Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites. REGISTRATION DETAILS: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.
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Lista de Checagem , Projetos de Pesquisa , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Literatura de Revisão como Assunto , Conferências de Consenso como AssuntoRESUMO
Clinical study protocols are the foundation of good clinical studies. Prospective and multidisciplinary collaboration that pays attention to the design of all components of the study protocol can ensure that a clinical study will answer the research questions posed in a reliable manner that is meaningful for decision-makers and patients. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials provides a framework for clinical study planning to ensure alignment between study objectives, design, conduct, and analysis. The estimand or clinical question posed can be regarded as the backbone of the study and the clinical study protocol should reflect estimands accordingly. In practice, stakeholders are still learning how to embrace the estimand framework and how it impacts studies and study documents. In this paper, we anticipate that a protocol structure centred around estimands, or objectives rather than endpoints alone will prevail for all types of studies. To assist sponsors during this paradigm shift, this paper provides discussion and guidance for implementing the estimand framework in protocol templates.
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Modelos Estatísticos , Projetos de Pesquisa , Interpretação Estatística de Dados , Humanos , Estudos ProspectivosRESUMO
A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single-centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic short-lasting unilateral neuralgiform headache attacks with MRI evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an 'excellent response', defined as 90-100% weekly reduction in attack frequency, or 'good response', defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients, of whom 31 had short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and 16 had short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. MRI of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Postoperatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing = 7 and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms = 3) reported no postoperative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks in the response to surgery (P = 0.463). Responders at the last follow-up were, however, more likely to not have interictal pain (77.42% versus 22.58%, P = 0.021) and to show morphological changes on the MRI (78.38% versus 21.62%, P = 0.001). The latter outcome was confirmed in the Kaplan-Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (P = 0.0001). All but one patient, who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for patients suffering short-lasting unilateral neuralgiform headache attacks with MRI evidence of neurovascular conflict with morphological changes.
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Cirurgia de Descompressão Microvascular , Síndrome SUNCT , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Síndrome SUNCT/cirurgiaRESUMO
INTRODUCTION: The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) remains challenging in view of the paucity of data and evidence-based treatment recommendations are missing. METHODS: In this single-centre, non-randomised, prospective open-label study, we evaluated and compared the efficacy of oral and parenteral treatments for SUNCT and SUNA in a real-world setting. Additionally, single-arm meta-analyses of the available reports of SUNCT and SUNA treatments were conducted. RESULTS: The study cohort comprised 161 patients. Most patients responded to lamotrigine (56%), followed by oxcarbazepine (46%), duloxetine (30%), carbamazepine (26%), topiramate (25%), pregabalin and gabapentin (10%). Mexiletine and lacosamide were effective in a meaningful proportion of patients but poorly tolerated. Intravenous lidocaine given for 7-10 days led to improvement in 90% of patients, whereas only 27% of patients responded to a greater occipital nerve block. No statistically significant differences in responders were observed between SUNCT and SUNA. In the meta-analysis of the pooled data, topiramate was found to be significantly more effective in SUNCT than SUNA patients. However, a higher proportion of SUNA than SUNCT was considered refractory to medications at the time of the topiramate trial, possibly explaining this isolated difference. CONCLUSIONS: We propose a treatment algorithm for SUNCT and SUNA for clinical practice. The response to sodium channel blockers indicates a therapeutic overlap with trigeminal neuralgia, suggesting that sodium channels dysfunction may be a key pathophysiological hallmark in these disorders. Furthermore, the therapeutic similarities between SUNCT and SUNA further support the hypothesis that these conditions are variants of the same disorder.
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Analgésicos/uso terapêutico , Anestésicos Locais/uso terapêutico , Anticonvulsivantes/uso terapêutico , Síndrome SUNCT/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Feminino , Humanos , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Síndrome SUNCT/complicações , Síndrome SUNCT/diagnóstico , Adulto JovemRESUMO
Emerging data-points towards a possible aetiological and therapeutic relevance of trigeminal neurovascular contact in short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and perhaps in short lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We aimed to assess the prevalence and significance of trigeminal neurovascular contact in a large cohort of consecutive SUNCT and SUNA patients and evaluate the radiological differences between them. The standard imaging protocol included high spatial and nerve-cistern contrast resolution imaging acquisitions of the cisternal segments of the trigeminal nerves and vessels. MRI studies were evaluated blindly by two expert evaluators and graded according to the presence, location and degree of neurovascular contact. The degree of contact was graded as with or without morphological changes. Neurovascular contact with morphological changes was defined as contact with distortion and/or atrophy. A total of 159 patients (SUNCT = 80; SUNA = 79) were included. A total of 165 symptomatic and 153 asymptomatic trigeminal nerves were analysed. The proportion of neurovascular contact on the symptomatic trigeminal nerves was higher (80.0%) compared to the asymptomatic trigeminal nerves (56.9%). The odds on having neurovascular contact over the symptomatic nerves was significantly higher than on the asymptomatic nerves [odds ratio (OR): 3.03, 95% confidence interval (CI) 1.84-4.99; P < 0.0001]. Neurovascular contact with morphological changes were considerably more prevalent on the symptomatic side (61.4%), compared to the asymptomatic side (31.0%) (OR 4.16, 95% CI 2.46-7.05; P < 0.0001). On symptomatic nerves, neurovascular contact with morphological changes was caused by an artery in 95.0% (n = 77/81). Moreover, the site of contact and the point of contact around the trigeminal root were respectively proximal in 82.7% (67/81) and superior in 59.3% (48/81). No significant radiological differences emerged between SUNCT and SUNA. The multivariate analysis of radiological predictors associated with the symptomatic side, indicated that the presence of neurovascular contact with morphological changes was strongly associated with the side of the pain (OR: 2.80, 95% CI 1.44-5.44; P = 0.002) even when adjusted for diagnoses. Our findings suggest that neurovascular contact with morphological changes is involved in the aetiology of SUNCT and SUNA. Along with a similar clinical phenotype, SUNCT and SUNA also display a similar structural neuroimaging profile, providing further support for the concept that the separation between them should be abandoned. Furthermore, these findings suggest that vascular compression of the trigeminal sensory root, may be a common aetiological factor between SUNCT, SUNA and trigeminal neuralgia thereby further expanding the overlap between these disorders.
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Transtornos da Cefaleia/diagnóstico por imagem , Síndrome SUNCT/diagnóstico por imagem , Nervo Trigêmeo/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anatomia Transversal , Atrofia , Estudos de Coortes , Feminino , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Dor/diagnóstico por imagem , Prevalência , Neuralgia do Trigêmeo , Adulto JovemRESUMO
Novel cell therapies for haematological malignancies and solid tumours address pressing clinical need while offering potentially paradigm shifts in efficacy. However, innovative development risks outflanking information on statutory frameworks, regulatory guidelines and their working application. Meeting this challenge, regulators offer wide-ranging expertise and experience in confidential scientific and regulatory advice. We advocate early incorporation of regulatory perspectives to support strategic development of clinical programmes. We examine critical issues and key advances in clinical oncology trials to highlight practical approaches to optimising the clinical development of cell therapies. We recommend early consideration of collaborative networks, early-access schemes, reducing bias in single-arm trials, adaptive trials, clinical end-points supporting risk/benefit and cost/benefit analyses, companion diagnostics, real-world data and common technical issues. This symbiotic approach between developers and regulators should reduce development risk, safely expedite marketing authorisation, and promote early, wider availability of potentially transformative cell therapies for cancer.
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Terapia Baseada em Transplante de Células e Tecidos/métodos , Ensaios Clínicos como Assunto , Neoplasias/terapia , Protocolos Clínicos , Humanos , Colaboração IntersetorialRESUMO
Master protocols have received a growing interest during the last years. By assigning patients to specific substudies, they aim at targeting and accelerating clinical development. Given their complexity, basket, umbrella, and platform designs have raised challenging regulatory and statistical questions, especially the control of multiplicity in confirmatory trials. In basket trials, regulatory assessment of the benefit/risk in pooled populations and choice of the treatment indication is challenging. We provide here our perspectives on these topics. In master protocols, as long as the statistical hypotheses tested between the different substudies are independent, no supplementary adjustment for multiplicity over the different substudies should be required. Moreover, sharing a control arm within an umbrella or a platform trial investigating different drugs would not require a correction for the type I error rate, whereas the chance of multiple false positive regulatory decisions should be recognized. In basket trials, pooling across substudies requires a rationale supporting the intended indication and should be preplanned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy/safety signals between the substudies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight into this novel framework.
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Ensaios Clínicos como Assunto/métodos , Interpretação Estatística de Dados , Projetos de Pesquisa , Ensaios Clínicos como Assunto/legislação & jurisprudência , HumanosRESUMO
Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.
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Linfoma Difuso de Grandes Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Criança , Humanos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genéticaRESUMO
OBJECTIVE: Despite the similar phenotypes, comparison between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic features (SUNA) has hitherto not been possible due to the dearth of studies validating the phenotype of SUNA. Therefore, these 2 syndromes have been kept separate in the International Classification of Headache Disorders. The aim of this study is to characterize and compare the clinical phenotypes of large clinic-based cohorts of patients with SUNA and SUNCT. METHODS: The clinical phenotype of consecutive patients with SUNA identified from a single specialist headache center in the United Kingdom between 2007 and 2012 was studied and compared to that of patients with SUNCT. RESULTS: Sixty-three patients with SUNA (18 male, 28.6%) and 70 patients with SUNCT (32 male, 35.7%) were included. The demographic and clinical characteristics of patients with SUNA were similar to those of patients with SUNCT. Ptosis and rhinorrhea were predictors of SUNCT. The corresponding odds ratios (ORs) (95% confidence interval) were 3.79 (1.64-8.77, p = 0.002) and 2.46 (1.09-5.59, p = 0.031), respectively. The presence of spontaneous only attacks was a predictor for SUNA (OR 2.58 [1.10-6.05], p = 0.029). CONCLUSION: No major clinical differences have emerged between SUNCT and SUNA, bar the fact that SUNCT is characterized by more prominent cranial autonomic features and triggerability. We propose that the 2 disorders be placed together in a single diagnostic category for which new diagnostic criteria are proposed.
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Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Síndrome SUNCT/diagnóstico , Síndrome SUNCT/fisiopatologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/diagnóstico , Neuralgia/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: Predictors of psychiatric outcome following TLE surgery have proved elusive and represent a current challenge in the practice of TLE surgery. This prospective study investigated whether frontal lobe dysfunction is predictive of poorer psychiatric outcomes. METHODS: Forty-nine unilateral TLE surgical patients were assessed using the Beck Depression Inventory-Fast Screen (BDI-FS) and Beck Anxiety Inventory (BAI) preoperatively and 6 and 12 months postoperatively. Measures of intellectual function, semantic knowledge, memory and executive function were completed preoperatively, at 6 and 12 months following surgery. RESULTS: Preoperatively, 33 (67%) patients had minimal depressive symptoms, 8 (16%) were mildly depressed, 2 (4%) were moderately depressed, and 6 (12%) reported severe depressive morbidity. Twenty-three (47%) patients reported minimal anxiety, 18 (37%) were mildly anxious, 6 (12%) were moderately anxious and 2 (4%) patients reported severe anxiety symptoms. A mixed-model repeated-measures analysis was performed on the BDI-FS and BAI scores, adjusting for pertinent covariates identified in univariable analyses. At a year following TLE surgery, anxiety symptoms significantly improved but depressive morbidity did not. Indicators of frontal lobe dysfunction moderated the magnitude and direction of mood change. Specifically, pre-surgical cognitive measures of frontal lobe dysfunction predicted increased depression and anxiety symptoms following surgery. There was no relationship between preoperative BDI-FS or BAI scores and seizure outcome at 12 months or change in affective morbidity and seizure outcome. SIGNIFICANCE: This is the first longitudinal study to provide evidence that specific pre-surgical cognitive and behavioural indices of frontal dysfunction are predictive of poorer psychiatric outcome following TLE surgery. In addition, our findings highlight the potential utility of a dysexecutive behavioural rating scale (DEX) as an assessment tool in epilepsy. Examination of executive functioning in pre-surgical evaluations may lead to an increase in the power of prognostic models used to predict the psychiatric outcome of TLE surgery.