RESUMO
BACKGROUND: Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF. OBJECTIVES: The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF. METHODS: The validated approach of this work consisted of a three-phase methodology: (i) generating the domains [systematic literature review (SLR) and qualitative studies]; (ii) agreeing (three-round international e-Delphi consensus process and working groups); and (iii) voting. RESULTS: (i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. (ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi process: 71 patients, relatives or representatives (31.0%), 130 healthcare professionals (HCPs, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. After round 2, five candidate items were excluded. Between rounds 2 and 3, international workshops were held to better understand the disagreements among stakeholders. This phase led to the identification of 19 items as outcome subdomains. (iii) The items were fused to create four outcome domains ('clinical assessment', 'daily life impact', 'patient satisfaction' and 'perception of health') and prioritized. The seven items that did not reach consensus were marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members. CONCLUSIONS: Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers four outcome domains that should be reported in all trial studies, agreed on by international patients, relatives and representatives of patients; HCPs; researchers, representatives of drug regulatory authorities or pharmaceutical companies and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed.
Assuntos
Neurofibroma , Neurofibromatose 1 , Neoplasias Cutâneas , Humanos , Técnica Delphi , Projetos de PesquisaRESUMO
BACKGROUND/AIMS: More than 99% of individuals with neurofibromatosis 1 develop cutaneous neurofibromas, benign nerve sheath tumors that manifest as nodules on the skin. These cutaneous neurofibromas emerge with age, appearing most commonly in adolescence. Nevertheless, few data have been published on how adolescents with neurofibromatosis 1 feel about cutaneous neurofibromas. The purpose of this study was to assess the perspectives of adolescents with neurofibromatosis 1 and their caregivers regarding cutaneous neurofibroma morbidity, treatment options, and acceptable risks-benefits of treatment. METHODS: An online survey was distributed through the world's largest NF registry. Eligibility criteria included self-reported neurofibromatosis 1 diagnosis, adolescent child ages 12-17 years, ≥1 cutaneous neurofibroma, and ability to read English. The survey was designed to collect details about the adolescent's cutaneous neurofibromas, views on morbidity related to cutaneous neurofibromas, social and emotional impact of cutaneous neurofibromas, communication regarding cutaneous neurofibromas, and views regarding current and potential future cutaneous neurofibroma treatment. RESULTS: Survey respondents included 28 adolescents and 32 caregivers. Adolescents reported having several negative feelings about cutaneous neurofibromas, particularly feeling worried about the potential progression of their cutaneous neurofibromas (50%). Pruritus (34%), location (34%), appearance (31%), and number (31%) were the most bothersome cutaneous neurofibroma features. Topical medication (77%-96%), followed by oral medication (54%-93%), was the most preferred treatment modality. Adolescents and caregivers most often replied that cutaneous neurofibroma treatment should be initiated when cutaneous neurofibromas become bothersome. The majority of respondents were willing to treat cutaneous neurofibromas for at least 1 year (64%-75%). Adolescent and caregivers were least willing to risk pain (72%-78%) and nausea/vomiting (59%-81%) as a cutaneous neurofibroma treatment side effect. CONCLUSIONS: These data indicate that adolescents with neurofibromatosis 1 are negatively impacted by their cutaneous neurofibromas, and that both adolescents and their caregivers would be willing to try longer-term experimental treatments.
Assuntos
Neurofibroma , Neurofibromatose 1 , Neoplasias Cutâneas , Criança , Adolescente , Humanos , Neurofibromatose 1/terapia , Neurofibromatose 1/patologia , Neurofibroma/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologia , Emoções , Inquéritos e QuestionáriosRESUMO
BACKGROUND/AIMS: We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity. METHODS: Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas (n = 20) and of untreated participants with plexiform neurofibromas (n = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability. RESULTS: Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control (p = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions (p > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment (r = 0.60). CONCLUSION: This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further.
Assuntos
Neurofibroma Plexiforme , Neurofibromatose 1 , Criança , Humanos , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).
Assuntos
Benzimidazóis/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Benzimidazóis/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Náusea/induzido quimicamente , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Dor/etiologia , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Carga Tumoral/efeitos dos fármacosRESUMO
Graft-versus-host disease (GVHD) is a multisystemic disorder that affects 30%-80% of patients who undergo allogeneic hematopoietic stem cell transplantation 10%-15% of GVHD patients develop sclerotic features affecting the skin or deeper tissues, leading to functional limitations and poor quality of life. There is limited literature regarding the indications and efficacy of specific rehabilitative interventions in sclerotic GVHD (sclGVHD). In this article, we summarize the current evidence supporting rehabilitation intervention in sclGVHD and offer our approach to the multidisciplinary management of this disease. In addition, we review techniques that have been employed in other sclerotic skin diseases (eg, iontophoresis, extracorporeal shock waves, botulinum toxin A, adipose derived stromal vascular fraction), but that require further validation in the sclGVHD setting. Ultimately, optimal care for this complex disease requires a multidisciplinary approach that includes a rehabilitation and adaptive program tailored to each patient's needs.
Assuntos
Doença Enxerto-Hospedeiro/reabilitação , Transplante de Células-Tronco Hematopoéticas , Terapia Ocupacional , Equipe de Assistência ao Paciente , Modalidades de Fisioterapia , Dermatopatias/reabilitação , Fáscia/patologia , Humanos , Qualidade de Vida , EscleroseRESUMO
Predicting the duration of systemic therapy in patients with chronic graft-versus-host disease (cGVHD) is of critical clinical importance when counseling patients and for treatment planning. cGVHD characteristics associated with this outcome have not been studied in severely affected patients. The National Institutes of Health (NIH) cGVHD scoring provides a standardized set of organ severity measures that could represent clinically useful and reproducible predictive characteristics. We analyzed 227 previously treated patients most with moderate (n = 54) or severe (n = 170) cGVHD defined by NIH criteria who were prospectively enrolled in a natural history protocol (NCT00092235). Patients received a median of 4 prior systemic therapy regimens and were seen at the NIH for a single time-point visit and were then monitored for survival and ability to discontinue cGVHD systemic therapy. With a median follow-up of 71.1 months, the cumulative incidence of systemic therapy discontinuation was 9.5% (95% confidence interval, 6.0% to 13.9%) at 2 years and 27.7% (95% confidence interval, 20.9% to 34.8%) by 5 years after the initial visit. Factors associated with a higher incidence of immunosuppression discontinuation included lower NIH global severity (P = .019) and lung (P = .030) scores and less extensive deep sclerosis (<37% body surface area, P = .024). Lower patient- and clinician-reported 0 to 10 severity NIH scores and noncyclosporine prophylaxis regimens were also associated with higher incidence of immunosuppression discontinuation (P <.05). In conclusion, we found low success rates for immune suppression discontinuation in previously treated patients who were severely affected with cGVHD. NIH scoring and clinical measures provide new standardized disease-specific tools to predict discontinuation of systemic therapy.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Adolescente , Adulto , Assistência ao Convalescente , Idoso , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
KEY TEACHING POINTS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Livedo Reticular/diagnóstico , Poliarterite Nodosa/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Fatores de Transcrição/deficiência , Adulto , Proteínas de Ligação a DNA , Diagnóstico Diferencial , Feminino , Humanos , Acidente Vascular Cerebral/prevenção & controle , Síndrome , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
In the past decade, the availability of powerful molecular techniques has accelerated the pace of discovery of several new primary immunodeficiencies (PIDs) and revealed the biologic basis of other established PIDs. These genetic advances, in turn, have facilitated more precise phenotyping of associated skin and systemic manifestations and provide a unique opportunity to better understand the complex human immunologic response. These continuing medical education articles will provide an update of recent advances in PIDs that may be encountered by dermatologists through their association with eczematous dermatitis, infectious, and non-infectious cutaneous manifestations. Part I will discuss new primary immunodeficiencies that have an eczematous dermatitis. Part II will focus on primary immunodeficiencies that greatly increase susceptibility to fungal infection and the noninfectious presentations of PIDs.
Assuntos
Eczema/epidemiologia , Eczema/terapia , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/terapia , Comorbidade , Eczema/diagnóstico , Educação Médica Continuada , Feminino , Terapia Genética/métodos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Incidência , Masculino , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Several primary immunodeficiencies (PIDs) have recently been described that confer an elevated risk of fungal infections and noninfectious cutaneous manifestations. In addition, immunologic advances have provided new insights into our understanding of the pathophysiology of fungal infections in established PIDs. We reviewed PIDs that present with an eczematous dermatitis in part I. In part II of this continuing medical education article we discuss updates on PIDs associated with fungal infections, their biologic basis in PIDs, and noninfectious cutaneous manifestations.
Assuntos
Candidíase Cutânea/epidemiologia , Candidíase Cutânea/patologia , Eczema/epidemiologia , Eczema/patologia , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/patologia , Candidíase Cutânea/diagnóstico , Candidíase Cutânea/terapia , Comorbidade , Eczema/diagnóstico , Eczema/terapia , Educação Médica Continuada , Feminino , Seguimentos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Incidência , Masculino , Terapia de Alvo Molecular/métodos , Índice de Gravidade de DoençaRESUMO
A 78-year-old Bulgarian woman presented to the National Institutes of Health (NIH) with a diagnosis of poorly differentiated metastatic carcinoma of unknown origin. The prior month she had been seen at a hospital in Bulgaria for weight loss and a right inguinal mass. NIH pathology review confirmed a poorly differentiated carcinoma with extensive necrosis suggesting squamous cell carcinoma. She was enrolled in a treatment trial at NIH with metastatic disease invading the lungs and lymph nodes (mediastinum, abdomen, and pelvis) and a chemotherapy regimen was started of gemcitabine, carboplatin, and lenalidomide with dexamethasone as an antiemetic. The patient returned on day 8, and a rash of 2 days duration was noted. Immediately before arriving at the dermatology clinic, she developed altered mental status with aphasia and was admitted for neurologic observation. The altered mental status resolved and evaluation revealed only small-vessel ischemia. The patient was also experiencing diarrhea and was found to have elevated transaminases (4- to 7-fold over normal). Chemotherapy was held because of the transaminase abnormalities and altered mental status. The following day, the patient was seen by dermatology for a progressive asymptomatic eruption.
Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias Primárias Desconhecidas/patologia , Dermatopatias Parasitárias/diagnóstico , Neoplasias Cutâneas/secundário , Strongyloides stercoralis/isolamento & purificação , Estrongiloidíase/diagnóstico , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Feminino , Seguimentos , Humanos , Hospedeiro Imunocomprometido , Ivermectina/uso terapêutico , Neoplasias Primárias Desconhecidas/imunologia , Medição de Risco , Dermatopatias Parasitárias/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Estrongiloidíase/tratamento farmacológico , Superinfecção/diagnóstico , Superinfecção/tratamento farmacológico , Superinfecção/imunologia , Visitas de Preceptoria , Resultado do TratamentoAssuntos
Dermatomicoses/etiologia , Foliculite/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos/terapia , Prurido/etiologia , Administração Tópica , Animais , Fármacos Dermatológicos/uso terapêutico , Dermatomicoses/patologia , Diagnóstico Diferencial , Dermatoses Faciais/etiologia , Dermatoses Faciais/patologia , Feminino , Foliculite/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Transtornos Linfoproliferativos/patologia , Ácaros/imunologia , Prurido/patologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: With the advent of the first targeted therapy for Rett Syndrome (RTT), a comprehensive assessment of the journey of RTT is needed to elucidate on present unmet needs in this population. This study characterized females with RTT in the United States and their disease journey with respect to longitudinal treatment patterns, RTT-related outcomes, and changes in disease severity. METHODS: This retrospective cohort study used registry data of females with RTT from the 5211 RTT Natural History Study (RNHS) (November 2015-July 2021). Pharmacological and supportive therapy use, RTT-related outcomes, and RTT severity, as measured by the Clinical Severity Scale and Motor Behavioral Assessment scale, were evaluated following the first RNHS visit. Analyses were conducted overall and in subgroups by RTT type (classic and atypical RTT) and age at first visit (pediatric and adult). RESULTS: A total of 455 females with RTT were included in the study, of whom 90.5% had classic RTT and 79.8% were pediatric individuals. Over a median follow-up of 4 years, use of pharmacological therapies, including prokinetic agents (42.7% vs. 28.3%), and supportive therapies, including physical therapy (87.3% vs. 40.2%) and speech-language therapy (86.8% vs. 23.9%), were more common in pediatric than adult individuals (all p < 0.05). Nearly half (44.6%) of all individuals had a hospital or emergency room visit, with a higher proportion of visits in individuals with classic RTT than atypical RTT and pediatric than adult individuals (both p = 0.001). An increasing trend in clinical severity was observed in pediatric individuals (mean change per year: 0.24; 95% confidence interval [CI]: 0.03, 0.44), while an increasing trend in motor-behavioral dysfunction was observed in pediatric individuals (mean change per year: 1.12; 95% CI: 0.63, 1.60) and those with classic RTT (mean change per year: 0.97; 95% CI: 0.53, 1.41). CONCLUSIONS: Findings from this study highlight the considerable burden of RTT across disease subtype and age. Despite reliance on supportive therapies and healthcare encounters, individuals with RTT experience increasing disease severity and motor-behavioral dysfunction in childhood and adolescence, underscoring the unmet needs of this population and the value of early intervention to manage RTT in the long-term.
Assuntos
Síndrome de Rett , Humanos , Síndrome de Rett/fisiopatologia , Síndrome de Rett/terapia , Síndrome de Rett/complicações , Feminino , Estados Unidos/epidemiologia , Adulto , Criança , Adolescente , Estudos Retrospectivos , Adulto Jovem , Pré-Escolar , Índice de Gravidade de Doença , Sistema de Registros , Lactente , Bases de Dados FactuaisAssuntos
Disceratose Congênita/genética , Disceratose Congênita/mortalidade , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Mucosa , Fenótipo , Estudos Prospectivos , Pele , Adulto JovemAssuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/parasitologia , Dermatofibrossarcoma/patologia , Hamartoma/patologia , Imunodeficiência Combinada Severa/parasitologia , Neoplasias Cutâneas/patologia , Agamaglobulinemia/diagnóstico , Biópsia por Agulha , Criança , Dermatofibrossarcoma/diagnóstico , Diagnóstico Diferencial , Feminino , Hamartoma/diagnóstico , Humanos , Imuno-Histoquímica , Doenças Raras , Imunodeficiência Combinada Severa/diagnóstico , Neoplasias Cutâneas/diagnósticoRESUMO
OBJECTIVE: To assess the perspectives of adults with neurofibromatosis 1 (NF1) regarding cutaneous neurofibroma (cNF) morbidity, treatment options, and acceptable risk-benefit ratio to facilitate the design of patient-centered clinical trials. METHODS: An online survey developed by multidisciplinary experts and patient representatives of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) cNF Working Group was distributed to adults with NF1 (n = 3,734) in the largest international database of individuals with any form of NF. Eligibility criteria included self-reported NF1 diagnosis, age ≥18 years, ≥1 cNF, and ability to read English. RESULTS: A total of 548 adults with NF1 responded to the survey. Respondents ranked appearance, number, and then location as the most bothersome features of raised cNF. Seventy-five percent of respondents considered a partial decrease of 33%-66% in the number or size of cNF as a meaningful response to experimental treatments. Most respondents (48%-58%) were willing to try available cNF treatments but were not aware of options outside of surgical removal. Regarding experimental agents, respondents favored topical, then oral medications. Most individuals (>65%) reported being "very much" or "extremely willing" to try experimental treatments, especially those with the highest cNF burden. Many respondents were not willing to tolerate side effects like nausea/vomiting (51%) and rash (46%). The greatest barriers to participation in cNF clinical trials were cost of participation and need to take time off work. CONCLUSIONS: Most adults with NF1 are willing to consider experimental therapies for treatment of cNF. These data will guide the design of patient-centered clinical trials for adults with cNF.
Assuntos
Ensaios Clínicos como Assunto , Neurofibroma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/metabolismo , Adolescente , Adulto , Doenças do Tecido Conjuntivo/terapia , Humanos , Neurilemoma/terapia , Neoplasias Cutâneas/terapia , Inquéritos e QuestionáriosRESUMO
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.
Assuntos
Adenosina Desaminase/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Adolescente , Adulto , Idoso , COVID-19/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Inibidores do Fator de Necrose Tumoral/metabolismo , Adulto JovemRESUMO
In 2005, the National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) consensus project provided diagnosis and staging criteria, based mostly on clinical experience and expert opinion. These criteria were revised in 2014, aiming to provide enhanced specificity and clarity. However, the impact of 2014 changes to the original NIH cGVHD severity scoring criteria has not been reported. In this study, 284 patients, prospectively enrolled on the National Cancer Institute's cross-sectional cGVHD natural history study, were scored using the 2005 NIH cGVHD criteria and then rescored according to the 2014 modifications. In comparing the two criteria, 2014 cGVHD global severity scoring resulted in a tendency toward being categorized as milder scores (75 vs. 72% of severe score per 2014, p = 0.0009), with a statistically significant shift in NIH liver and lung scores toward milder categories (p < 0.0001). 2005 and 2014 NIH global severity scores showed a significant association with reduced grip strength (p < 0.0001), reduced joint range of motion (p = 0.0003), and the subspecialist evaluation score (p < 0.0001). Poor survival prediction of the severe NIH lung score is also retained in the new criteria (p = 0.0012). These findings support the use of 2014 cGVHD scoring criteria in continuous efforts to develop better classification systems.
Assuntos
Doença Enxerto-Hospedeiro , Hepatopatias , Índice de Gravidade de Doença , Adulto , Idoso , Doença Crônica , Estudos Transversais , Feminino , Doença Enxerto-Hospedeiro/classificação , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Hepatopatias/classificação , Hepatopatias/patologia , Hepatopatias/fisiopatologia , Pneumopatias/classificação , Pneumopatias/patologia , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Estados UnidosRESUMO
OBJECTIVE: A group of experts in dermatology, genetics, neuroscience, and regenerative medicine collaborated to summarize current knowledge on the defined factors contributing to cutaneous neurofibroma (cNF) development and to provide consensus recommendations for future research priorities to gain an improved understanding of the biology of cNF. METHODS: The group members reviewed published and unpublished data on cNF and related diseases via literature search, defined a set of key topic areas deemed critical in cNF pathogenesis, and developed recommendations in a series of consensus meetings. RESULTS: Five specific topic areas were identified as being relevant to providing an enhanced understanding of the biology of cNF: (1) defining the human cells of origin; (2) understanding the role of the microenvironment, focusing on neurons, mast cells, and fibroblasts; (3) defining the genetic and molecular differences between the cNFs, focusing on size and number; (4) understanding if sex hormones are critical for cNF development or progression; and (5) identifying challenges in establishing in vitro and in vivo models representing human cNF. CONCLUSIONS: The complexity of cNF biology stems from its heterogeneity at multiple levels including genetic, spatial involvement, temporal development, and cellular composition. We propose a unified working model for cNF that builds a framework to address the key questions about cNF that, when answered, will provide the necessary understanding of cNF biology to allow meaningful development of therapies.